bims-axbals Biomed News
on Axonal biology and ALS
Issue of 2026–05–03
47 papers selected by
TJ Krzystek
  1. Human iPSC-Derived Dorsal Root Ganglion Organoid Modeling of Chemotherapy-Induced Peripheral Neuropathy.
  2. Tubulin polyglutamylation modulates Golgi morphodynamics and neurite branching during neuronal morphogenesis.
  3. Cell death detection in iPSC-derived cortical neurons as model of neurodegeneration.
  4. Lysosome-Acidifying Nanoparticles Rescue A30P α-Synuclein Induced Neuronal Death in Cellular and Drosophila Models of Parkinson's Disease.
  5. SPG11 models reveal lysosomal calcium regulation of neural progenitor proliferation.
  6. Treatment of Huntington's disease with a pan-HTT-targeting CRISPR nuclease.
  7. Mechanistic dissection of BLTP2 targeting to ER-PM contact sites.
  8. Direct targeting of C9ORF72 repeat RNA with fluorinated antisense oligonucleotides.
  9. Purkinje cell-specific loss of Neurofascin and Ankyrin G causes disruption of axon initial segments, neurodegeneration, and cerebellar ataxia.
  10. Neuronal extracellular vesicles regulate axon development in primary cortical neurons via local miR-99a targeting of HS3ST2.
  11. A standardized framework resolves ambiguity in motor neuron loss across neurodegenerative diseases.
  12. Physiological and pathological functions of TAF15 in neurodegenerative diseases and cancers.
  13. Caffeic Acid Phenethyl Ester Enhanced the Klotho/SIRT1/Nrf2/HO-1 Axis to Protect Against Methylmercury-Induced ALS-Like Neurodegeneration.
  14. A High-Throughput Live Imaging Platform to Investigate Circuit-Dependent Regulation of Circadian Rhythms in Brain Tissue.
  15. AhR inhibition promotes axon regeneration.
  16. Electrochemical measurements at human iPSC-derived FOXA2 dopaminergic neurons suggest a role for partial release in presynaptic plasticity.
  17. The Recycling Endosomal (Na+, K+)/H+ Exchanger NHE6/SLC9A6 Facilitates Signal Transduction by Shuttling Cyclin-Dependent Kinase 5 to the Plasma Membrane.
  18. Interference of Large Clostridial Glucosyltransferases with the Endolysosomal Pathway: Toxin-Induced Imbalance of Early Endosomes, Functional Lysosomes and Autophagosomes.
  19. Iloperidone treatment mitigates the Juvenile Huntington's Disease phenotype possibly via Sigma-1 Receptor Modulation.
  20. Statins and genetic inhibition of the mevalonate pathway activate an ATF3-STMN2 regenerative program.
  21. Mitochondrial DNA replication is regulated by endoplasmic reticulum-mitochondrial contact sites, the mitochondrial calcium uniporter, and manganese.
  22. Protocol for culture and maintenance of canine induced pluripotent stem cells.
  23. Sorcin couples Annexin A11 recruitment and ESCRT-III assembly during plasma membrane repair.
  24. Developmental regulation of kinetochore phosphorylation determines mitotic fidelity.
  25. Protocol for generating iPSC-derived intestinal organoids through dissection to model cystic fibrosis therapies.
  26. Autophagy: mechanisms, roles in human diseases, and therapeutic perspectives.
  27. mTOR Signalling in Neurodegenerative Disorders: Unveiling Key Factors, Mechanistic Insights, and Possible Therapeutic Interventions.
  28. Individualized phenotyping of functional amyotrophic lateral sclerosis pathology in sensorimotor cortex.
  29. Modulating microtubule stability via α-tubulin acetylation partially restores Golgi fragmentation in spinal muscular atrophy.
  30. An Inducible hiPSC-Derived Human Podocyte Model for Functional Analysis of TRPC6 Variants Associated with FSGS.
  31. The interaction between exercise and autophagic flux in neurodegenerative muscle loss.
  32. Computational Pathology as a Mechanistic Discipline: From Morphology to Molecular Data.
  33. Quantitative live imaging reveals PRICKLE1 controls junctional neural tube morphogenesis independent of Planar Cell Polarity.
  34. Lipids Regulate Export of Lysosomal Enzymes from the Endoplasmic Reticulum.
  35. Impaired phrenic nerve axon development and diaphragm neuromuscular junction formation in embryonic Cyfip2-null mice.
  36. A robust workflow for 3D imaging of human mitochondria using cryo-electron tomography.
  37. Brain Organoids: Emerging Platforms for Modern Neuroscience.
  38. Augmented and prematurely occurring H-reflex recovery curve shows enhanced spinal network excitability in ALS patients when employing the double stimulation paradigm.
  39. From stability to pathology: protein degradation pathways underlying synaptic proteins in neurological diseases.
  40. Advances in Cell Therapy for Neural Repair.
  41. Multi-omic phenotyping of MAPT V337M neurons reveals early changes in axonogenesis and tau phosphorylation.
  42. FTDP-17T Mutations Promote Formation of Phosphorylated FTDP-17T TAU Oligomers That Cause Degeneration of Dopaminergic and Hippocampal Neurons via Activating ER Stress and Mitochondrial Pro-apoptotic Cascades.
  43. The exocyst is an insulin-sensitive regulator of amyloid precursor protein trafficking and amyloid-beta generation in neurons.
  44. A new dawn for Parkinson's disease: commentary on the emergence of stem cell-based therapies.
  45. In Vitro Reconstruction of Axonal Heat Sensing with a Photothermal Nerve-on-a-Chip.
  46. Next-Generation Strategies for Neural Repair and Regeneration: Neural Organoid Transplantation in the CNS.
  47. Lysosomal Profiling with LysoTracker for Quantitative Assessment of Cellular Senescence in Human Fibroblasts.
  1. Cells. 2026 Apr 19. pii: 724. [Epub ahead of print]15(8):
    Human iPSC-Derived Dorsal Root Ganglion Organoid Modeling of Chemotherapy-Induced Peripheral Neuropathy.
    Sybil C L Hrstka, Maya Jahnke, Kylie Meng-Lin, Sarah Lindorfer, Henry Noma, Ronald F Hrstka, Nathan P Staff.
      Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity affecting 30-40% of patients treated with neurotoxic chemotherapy. Sensory symptoms arise from injury to dorsal root ganglion (DRG) neurons and their axons; yet, the underlying mechanisms remain incompletely understood. While human induced pluripotent stem cell (iPSC)-derived sensory neuron (iSN) monolayers have provided mechanistic insight, they lack the three-dimensional architecture and cellular heterogeneity of native DRG tissue. Here, we generated human iPSC-derived DRG organoids (iDRGOs) containing mixed neuronal and peripheral glial populations and established a quantitative neurite outgrowth assay to model chemotherapy-induced neurotoxicity in a 3D context. iDRGOs from three healthy donors were exposed to bortezomib, vincristine, or paclitaxel. All three drugs caused dose-dependent neurite outgrowth impairment without significant short-term changes in organoid size, consistent with early axonal injury. Vincristine reduced MAP2 levels when normalized to total protein, whereas bortezomib and paclitaxel showed divergent microtubule-associated responses compared to monolayer cultures. The developmental stage significantly influenced the baseline neurite outgrowth, highlighting the need for age standardization. These results establish iDRGOs as a physiologically relevant human platform that complements monolayer models for mechanistic studies and therapeutic screening in CIPN.
    Keywords:  chemotherapy-induced neurotoxicity; dorsal root ganglion; iPSC; organoid
    DOI:  https://doi.org/10.3390/cells15080724
  2. bioRxiv. 2026 Apr 14. pii: 2026.04.13.718193. [Epub ahead of print]
    Tubulin polyglutamylation modulates Golgi morphodynamics and neurite branching during neuronal morphogenesis.
    Chih-Hsuan Hsu, Alexander Josiah Kinrade, Sarah Cohen.
      Neurons establish functional networks through morphological remodeling during neuronal differentiation. Microtubule polyglutamylation is a key microtubule post-translational modification that is highly enriched during this process and plays an important role in differentiation. However, how remodeling of organelle features such as morphology, distribution and interactions depend on tubulin polyglutamylation during neuronal differentiation remain unclear. Here, we employed multispectral imaging combined with quantitative 3D organelle analysis to comprehensively profile eight organelles simultaneously in human induced pluripotent stem cell-derived neurons. We discovered that depletion of tubulin polyglutamylation induces pronounced alterations in somatic Golgi morphology and associated organelle interactions. In addition, Golgi-derived compartments in proximal neurites exhibited altered morphology and dynamics, namely decreased retrograde directionality. These changes were accompanied by increased neurite branching and tortuosity. Together, our findings reveal a previously unrecognized role for tubulin polyglutamylation in coordinating organelle organization with neurite architecture, providing a mechanistic link between tubulin post-translational modification, Golgi morphology, dynamics, and neuronal morphogenesis.
    DOI:  https://doi.org/10.64898/2026.04.13.718193
  3. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00089-0. [Epub ahead of print]206 217-233
    Cell death detection in iPSC-derived cortical neurons as model of neurodegeneration.
    Fiorella Colasuonno, Manuela D'Eletto, Veronica Bellanca, Mauro Piacentini, Federica Di Sano, Federica Rossin.
      Induced pluripotent stem cells (iPSCs) represent an innovative tool to model neurodegenerative disorders, providing access to disease-relevant cell types such as neurons that are otherwise inaccessible. In the context of Alzheimer's disease (AD), iPSC-derived neural cultures offer a unique opportunity to investigate pathological mechanisms in a controlled environment, overcoming limitations of animal models. Central to AD pathogenesis is the amyloid cascade hypothesis, which is based on the concept that accumulation and aggregation of the toxic oligomeric species, initiates a cascade of events leading to synaptic dysfunction, neuronal loss, and cognitive decline. It is known that application of the Aβ oligomers to neurons reproduces key features of synaptic impairment, preceding overt neuronal death. In this study, we proposed an optimized protocol employing iPSC-derived neurons exposed to Aβ1-42 peptide. This approach provides a clear and reliable method to evaluate neurotoxic effects of Aβ peptide on neuronal morphology and viability. Indeed, on the one hand neuronal morphology, assessed through immunofluorescence using specific neuronal markers, allows precise monitoring of neurite length and synaptic connectivity, crucial parameters to evaluate neuronal health. On the other hand, cytotoxicity is directly quantified using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, which confirm Aβ-induced neuronal injury. Notably, this combined approach provides novel insights into early Aβ-driven neurodegenerative processes and offers a platform to identify therapeutic strategies targeting the initial phases of AD pathology.
    Keywords:  AD; Aβ 1–42; IPSC-derived neurons; Neurodegeneration; Neurotoxicity; TUNEL
    DOI:  https://doi.org/10.1016/bs.mcb.2026.02.021
  4. Adv Healthc Mater. 2026 Apr 25. e02906
    Lysosome-Acidifying Nanoparticles Rescue A30P α-Synuclein Induced Neuronal Death in Cellular and Drosophila Models of Parkinson's Disease.
    Chih Hung Lo, Mengda Ren, Gavin Wen Zhao Loi, Eka Norfaishanty Saipuljumri, Jonathan Indajang, Kah Leong Lim, Jialiu Zeng.
      Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting over 10 million people worldwide. It is characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the accumulation of misfolded α-synuclein (αSyn) in intracellular inclusions known as Lewy bodies. Emerging evidence links αSyn accumulation to impaired lysosomal acidification and defective autophagy-lysosomal degradation, which are central to disease progression. To address this lysosomal dysfunction, we engineered a novel type of lysosome-targeted acidic nanoparticles (AcNPs) based on a biodegradable copolymer, poly(ethylene tetrafluorosuccinate-co-succinate) (PEFSU). These nanomaterials were developed to locally acidify impaired lysosomes and restore their degradative capacity. We evaluated their therapeutic potential in two familial PD models: SH-SY5Y neuroblastoma cells overexpressing A30P αSyn and A30P αSyn transgenic Drosophila melanogaster. In vitro, AcNPs effectively restored lysosomal pH, enhanced autophagic clearance of αSyn, improved mitochondrial function, and rescued A30P αSyn-induced cytotoxicity. In vivo, AcNPs treatment reduced αSyn burden, preserved dopaminergic neurons, and improved motor function in flies. This study demonstrates the first application of lysosome-acidifying polymeric nanoparticles in familial PD models and highlights the promise of rationally engineered pH-modulating nanomaterials as therapeutic agents for PD and other neurodegenerative diseases driven by lysosomal dysfunction and protein aggregation.
    Keywords:  acidic nanoparticles; autophagy; dopaminergic neurons; familial Parkinson's disease; locomotor activity; lysosomal acidification; α‐synuclein
    DOI:  https://doi.org/10.1002/adhm.202502906
  5. Neurobiol Dis. 2026 Apr 26. pii: S0969-9961(26)00168-3. [Epub ahead of print] 107423
    SPG11 models reveal lysosomal calcium regulation of neural progenitor proliferation.
    Dominic Samaroo, Margaux Cauhape, Léa Bernachot, Salomé Moulière, Frédéric Darios.
      Lysosome dysfunction has been widely implicated in many models of neurodegeneration, but much less is understood of its involvement during brain development in health and disease. Hereditary spastic paraplegia caused by mutations in the SPG11 gene is a neurodegenerative disorder characterized by lysosome dysfunction, which also presents neurodevelopmental alterations. Using knockout mouse and cortical organoid models derived from induced pluripotent stem cells, we show that lysosome dysfunction caused by SPG11 mutations decreases the proliferation of neural progenitor cells at early stages of cortical development. At the cellular level, SPG11 mutations cause accumulation of calcium in lysosomes, which reduces proliferation of neural progenitor cells and diminishes apical tight junctions. RNA sequencing analysis revealed that these phenotypes in SPG11 organoids are caused by hypoactivation of mammalian target of rapamycin (mTOR) signaling. The latter is a consequence of lysosomal recruitment of the enzyme PI4K2A (phosphatidylinositol 4-kinase type 2 alpha) resulting in higher levels of its product PI(4)P (phosphatidylinositol-4-phosphate), a described regulator of the mTOR pathway. Pharmacological modulation of the function of the lysosomal calcium channel TRPML1 successfully corrected all developmental phenotypes in cortical organoids, highlighting the critical role of lysosomal calcium in signaling during the early phase of cortical development.
    Keywords:  Calcium; Cortical organoids; Lysosome; Neurodegeneration; Neurodevelopment
    DOI:  https://doi.org/10.1016/j.nbd.2026.107423
  6. Mol Ther. 2026 Apr 24. pii: S1525-0016(26)00303-5. [Epub ahead of print]
    Treatment of Huntington's disease with a pan-HTT-targeting CRISPR nuclease.
    Katherine Tan, Daniela Del Bosque Siller, Alisha Y Xiong, Anna X A Wang, Tristan X McCallister, Sreya Mummadi, Luke A St John, Tae Kyu Lee, Annika Carrillo, Daniel G Renshaw, Richard H Zhou, Colin K W Lim, Jack He, Christopher J Fields, Michael R Hayden, Thomas Gaj.
      Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene, which leads to a mutant protein that destroys neurons in the brain. Despite intense effort, there remains no approved disease-modifying therapy for HD. Here we develop a pan-HTT-targeting CRISPR-Cas9 system that, when delivered to the striatum of R6/2 and YAC128 mice by AAV5, lowered mutant HTT mRNA and protein by 55-80% via its induction of frameshift-inducing indel mutations in HTT exon 1. Cas9 targeting improved motor coordination and locomotor activity, decreased anxiety-like deficits, reduced clasping and weight loss, limited striatal atrophy, and decreased the formation of intranuclear inclusions immunoreactive for the mutant HTT protein. In Hu21/21 mice, which carry the wild-type human HTT gene in lieu of the mouse ortholog, Cas9 lowered the HTT protein by 44% but induced no measurable behavioral deficits and had no adverse effect on neuronal viability, though its targeting was associated with neuroinflammation. Altogether, our results demonstrate the ability for a newly developed pan-HTT-targeting Cas9 system to affect HD-related phenotypes across models and provide insights into its tolerability.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.04.038
  7. bioRxiv. 2026 Apr 13. pii: 2026.04.12.718032. [Epub ahead of print]
    Mechanistic dissection of BLTP2 targeting to ER-PM contact sites.
    Sarah D Neuman, Amy T Cavanagh, Nicole Sheffels, Elizabeth Conibear, Arash Bashirullah.
      The bridge-like lipid transfer proteins (BLTPs) are a novel superfamily of rod-shaped lipid transporters that engage in bulk non-vesicular movement of lipids at organelle membrane contact sites. The molecular and cellular functions of these proteins are still emerging; however, it is clear that one key aspect that regulates BLTP function is targeting to the appropriate membrane contact site(s). Here, we use Drosophila as a model system to dissect the mechanisms that drive targeting of BLTP2 ( hobbit in Drosophila ) to endoplasmic reticulum-plasma membrane (ER-PM) contact sites. We demonstrate that a conserved adapter protein, which we name bilbobaggins ( bbo ), is required for targeting of Hobbit to ER-PM contacts; importantly, loss of bbo phenocopies loss of hobbit , indicating that bbo is required for hobbit function. Additionally, our structure-function analyses show that cis -acting sequences in the C-terminal tail of Hobbit are also required for ER-PM targeting. Crucially, our data indicates that that these cis -acting sequences and Bbo binding are independent and likely sequential mechanisms that we propose function like a "hook" and "latch" to govern Hobbit targeting. Thus, we define a new regulatory paradigm governing targeting of BLTPs to membrane contact sites.
    DOI:  https://doi.org/10.64898/2026.04.12.718032
  8. Nucleic Acids Res. 2026 Apr 23. pii: gkag343. [Epub ahead of print]54(8):
    Direct targeting of C9ORF72 repeat RNA with fluorinated antisense oligonucleotides.
    Halle M Barber, Mansi A Parasrampuria, Jerónimo Jurado-Arjona, Andrea Gamir-Morralla, Benedikt Berninger, Carlos González, Keith T Gagnon, Masad J Damha, Miguel Garavís.
      Hexanucleotide repeat expansions in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. These expansions give rise to pathogenic sense and antisense repeat RNAs that form nuclear foci and undergo repeat-associated non-AUG translation, producing dipeptide repeat proteins with cellular toxicity. Directly targeting the causative repeat RNAs with antisense oligonucleotides represents a promising therapeutic strategy. One barrier to further development is the propensity of this G-rich repeat-containing RNA target to form stable secondary structures, which may hinder efficient hybridization. In this study, we designed a panel of fluorine-modified ASOs that target the sense repeat expansions. We identified C-rich F-ASO gapmers that reduced translation from sense repeat RNAs in a cell-based reporter assay and lowered the RNA foci burden in patient-derived cells. Structural analyses in vitro revealed that the 2'F-RNA gapmer formed a stable hairpin structure. Our results demonstrate that structural properties of fluorine modifications can be leveraged for effective binding of repeat RNA and highlight the potential for F-ASOs to serve as therapeutic tools when targeting toxic repeat RNAs in C9ORF72-mediated FTD/ALS and other repeat expansion diseases.
    DOI:  https://doi.org/10.1093/nar/gkag343
  9. Front Cell Neurosci. 2026 ;20 1690466
    Purkinje cell-specific loss of Neurofascin and Ankyrin G causes disruption of axon initial segments, neurodegeneration, and cerebellar ataxia.
    Qian Shi, Anna M Taylor, Lacey B Sell, Manzoor A Bhat.
      The axon initial segment (AIS) is essential for initiating action potentials and maintaining neuronal polarity, yet the developmental roles of its core molecular components-Neurofascin 186 (NF186) and Ankyrin G (AnkG)-remain incompletely defined in cerebellar Purkinje cells. Here, we generated Purkinje cell-specific NF186 and AnkG single- and double-knockout mice to investigate how these adhesion and scaffolding proteins cooperatively regulate AIS formation, ion channel localization, synaptic targeting, and neuronal survival. We found that genetic ablation of either Nfasc NF186 (NFKO) or Ankyrin3 (AnkGKO) disrupted assembly and maintenance of the AIS cytoskeleton, and that this defect was exacerbated by combined loss of both proteins during postnatal development. Other AIS-enriched proteins, including βIV Spectrin (βIVSpec), voltage-gated sodium (Nav), and potassium (Kv1.2) channels, failed to properly localize to the AIS and progressively disintegrated between postnatal days 10 and 30. Notably, Kv1.2 clustering at the pinceau synapse was disrupted, and basket cell axons showed misaligned terminal organization, indicating defective inhibitory synapse innervation. By 2 months of age, degeneration of Purkinje cells was evident, accompanied by cerebellar dysfunction. Notably, AnkG ablation caused a progressive postnatal loss of NF186 at the AIS, whereas NF ablation resulted in much slower loss of AnkG at the AIS in Purkinje cells and closely phenocopied the severe AIS destabilization observed in NF/AnkG double-knockout mice. In addition, our RNA-seq analysis revealed that Purkinje cell-specific loss of NF186 predominantly activated immune-inflammatory pathways; AnkG loss significantly disrupted neuronal developmental and metabolic processes; and the dual loss of NF186/AnkG produced transcriptional changes that were distinct from, and in part intermediate to, those observed in NF186 and AnkG single knockout. Collectively, our results show that NF186 and AnkG have complementary, non-redundant roles in establishing and maintaining the Purkinje cell AIS, and that their loss disrupts synaptic organization at the AIS. These findings advance our understanding of AIS development in cerebellar neurons and have implications for diseases involving AIS dysfunction, including cerebellar ataxia and demyelinating neuropathies.
    Keywords:  Ankyrin G; Neurofascin 186; Purkinje cells; axon initial segment; cerebellum; neurodegeneration; pinceau organization
    DOI:  https://doi.org/10.3389/fncel.2026.1690466
  10. Mol Biol Cell. 2026 Apr 29. mbcE25120581
    Neuronal extracellular vesicles regulate axon development in primary cortical neurons via local miR-99a targeting of HS3ST2.
    Raquel Mesquita-Ribeiro, Alex Rathbone, Paula Jackson, Sophie McCann, Hannah Jackson, Cristiano Lucci, Victoria James, Clare Coveney, David Boocock, Federico Dajas-Bailador.
      Fully functional neural competence and integrity requires a complex array of communication means among neurons, with extracellular vesicles (EVs) emerging as a relevant mechanism for cell-cell interaction in the CNS. Despite the growing number of studies demonstrating the presence of microRNAs (miRNAs) in axon and EVs, the molecular mechanisms of those miRNAs present in EVs and their functional role in nervous system development has not been fully explored. In this study, we investigated whether neuronal EVs can have a role in neuron-to-neuron communication during the development of neuron connectivity in mouse primary cortical neuron cultures. Our results demonstrate how miR-99a can regulate axonal growth via its EV-mediated delivery and through the targeting of HS3ST2, a heparan sulphate glucosamine 3-O-sulphotransferase, which is predominantly expressed in the brain and generates rare 3-O-sulphated domains in heparan sulphate proteoglycans, with growing importance in development and neurodegenerative mechanisms. Importantly, we show how in compartmentalised microfluidic cultures, where axons are isolated from neuronal somas, the growth-promoting effects of neuron-derived EVs are local to the axon. These findings establish that neuronal EVs can deliver miRNAs to discrete subcellular domains to acutely modulate local gene expression, thereby driving axonal growth and shaping neurodevelopment.
    DOI:  https://doi.org/10.1091/mbc.E25-12-0581
  11. bioRxiv. 2026 Apr 18. pii: 2026.04.15.718647. [Epub ahead of print]
    A standardized framework resolves ambiguity in motor neuron loss across neurodegenerative diseases.
    Leonie Sowoidnich, Aaron L Norman, Florian Gerstner, Josiane K Siemund, Jannik M Buettner, John G Pagiazitis, Vanessa Dreilich, Konstantin Pilz, Dajun Tian, Charlotte J Sumner, Angela Paradis, George Z Mentis, Christian M Simon.
      Motor neuron (MN) loss is a hallmark of neurodegenerative disorders, yet its assessment remains variable, confounding mechanistic and therapeutic interpretation. To address this, we conducted a systematic review and meta-analysis of spinal muscular atrophy (SMA) mouse studies, revealing 60% variability in reported MN loss, largely attributable to nonspecific spinal cord sampling. Using a whole-segment approach with tissue clearing, MN tracing, and multimodal imaging, we confirmed segment-dependent differences in MN counts. Common MN markers (SMI-32, Nissl) lacked specificity, whereas choline acetyltransferase (ChAT) provided robust labeling in murine and human spinal cords. Deep learning-based whole-mount segmentation enabled unbiased MN quantification and validated manual counts. Integrating analysis with computational modeling established segment sampling as a key driver of variability and revealed degeneration patterns: widespread MN loss in amyotrophic lateral sclerosis (ALS), selective MN loss in severe SMA, and preservation in mild SMA models. These findings establish a framework for reproducible MN quantification.
    Highlights: Spinal cord segment-specific analysis reduces variability and allows accurate MN quantificationChAT is the most reliable MN marker in murine and human spinal cordsDeep learning-based segmentation enables unbiased MN quantification in intact spinal cordsMN degeneration is widespread in ALS but restricted to pools innervating proximal muscles in severe SMA.
    DOI:  https://doi.org/10.64898/2026.04.15.718647
  12. J Adv Res. 2026 Apr 26. pii: S2090-1232(26)00370-X. [Epub ahead of print]
    Physiological and pathological functions of TAF15 in neurodegenerative diseases and cancers.
    Congcong Liu, Lanxia Meng, Zhentao Zhang.
       BACKGROUND: TATA-box binding protein associated factor 15 (TAF15) is a multifunctional DNA/RNA-binding protein that plays pivotal roles in transcription regulation, precursor mRNA splicing, and cellular stress responses. Accumulating evidence demonstrates that TAF15 is strongly implicated in two distinct pathological classes: neurodegenerative diseases and cancers. In neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), TAF15 undergoes abnormal cytoplasmic aggregation and mislocalization in neurons and glia, and TAF15 has been established as a candidate disease gene for ALS. In a wide range of cancers, TAF15 drives oncogenic transcriptional dysregulation either via wild-type protein dysfunction or the formation of oncogenic fusion proteins derived from chromosomal translocations.
    AIM OF REVIEW: A central unresolved question is how TAF15 contributes to two mechanistically distinct disease entities. This review aims to provide a mechanistically integrated analysis of the physiological and pathological functions of TAF15. We use TAF15's intrinsic molecular properties as a unifying framework to connect its roles in neurodegeneration and cancer. We also summarize key pathogenic mechanisms and emerging therapeutic strategies targeting TAF15, with the goal of proposing a novel conceptual perspective to guide future research. Key scientific concepts of review. TAF15 may act as a biologically relevant molecular link between neurodegeneration and cancer through its intrinsic molecular characteristics, such as nucleic acid binding, phase separation, and nucleocytoplasmic shuttling. The "localization determines outcome" hypothesis offers a unifying framework to explain the connection between the two diseases. TAF15 holds promise as a target for novel biomarkers and precision therapeutics across both disease areas. Deepening mechanistic studies of TAF15 will not only advance understanding of its dual pathological roles but also illuminate the largely unexplored molecular link between neurodegenerative diseases and cancers.
    Keywords:  Cancer; Neurodegenerative disease; RNA-binding protein; TATA-box binding protein associated factor 15 (TAF15)
    DOI:  https://doi.org/10.1016/j.jare.2026.04.066
  13. Mol Neurobiol. 2026 Apr 27. pii: 590. [Epub ahead of print]63(1):
    Caffeic Acid Phenethyl Ester Enhanced the Klotho/SIRT1/Nrf2/HO-1 Axis to Protect Against Methylmercury-Induced ALS-Like Neurodegeneration.
    Ravi Rana, Sidharth Mehan, Ritam Mukherjee, M D Nasiruddin Khan, Ghanshyam Das Gupta, Acharan S Narula.
      Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by motor neuron degeneration, oxidative stress, and neuroinflammation. This study evaluated the neuroprotective potential of caffeic acid phenethyl ester (CAPE) against MTME + 5-induced neurotoxicity in an ALS-like pathology model. CAPE (50 and 100 mg/kg., p.o.) demonstrated significant therapeutic efficacy by improving motor and cognitive deficits, restoring oxidative balance, and mitigating neuroinflammatory and apoptotic pathways. Behavioral assessments, including the open field, grip strength, forced swim, and Morris water maze, highlighted CAPE's ability to restore neuromuscular coordination and cognitive function in a dose-dependent manner. Cellular and Molecular analyses revealed that MTME+5 exposure significantly disrupted Klotho/SIRT-1/Nrf2/HO-1 antioxidant signaling, increased pro-inflammatory cytokines (TNF-α, IL-1β), and elevated apoptotic markers (Bax, caspase-3) while depleting anti-inflammatory cytokines (IL-10) and neuroprotective proteins. Furthermore, CAPE treatment restored these parameters, reduced oxidative stress, and enhanced antioxidant defenses (SOD, CAT, r-GSH). Furthermore, CAPE normalized neurotransmitter imbalances, including acetylcholine, dopamine, GABA, serotonin, and glutamate, alleviating excitotoxicity. Histopathological and gross morphological analyses confirmed CAPE50 and CAPE100 ability to preserve neuronal and myelin integrity across key brain regions, including the cerebral cortex, hippocampus, striatum, midbrain, and cerebellum. CAPE also reduced methylmercury accumulation in the brain and cerebrospinal fluid, indicating detoxifying effects. Co-administration of vitamin B1 (VTB1(200)) further amplified CAPE's therapeutic efficacy. Complete blood count (CBC) analysis demonstrated MTME+5-induced hematological abnormalities, including reduced RBCs, hemoglobin, WBCs, and platelets, alongside elevated eosinophils and basophils. CAPE treatment normalized these parameters, indicating systemic recovery. These findings establish CAPE as a promising neuroprotective agent for ALS, capable of targeting neurocomplications.
    Keywords:  Amyotrophic lateral sclerosis (ALS); Caffeic acid phenethyl ester (CAPE); Demyelination; Klotho/SIRT-1/Nrf2/HO-1 signaling; Methylmercury; Neuroprotection
    DOI:  https://doi.org/10.1007/s12035-026-05871-3
  14. Adv Sci (Weinh). 2026 Apr 28. e75427
    A High-Throughput Live Imaging Platform to Investigate Circuit-Dependent Regulation of Circadian Rhythms in Brain Tissue.
    Marco Ferrari, Natalie Ness, Julieta Acosta, Marco Brancaccio.
      Circadian function in multicellular organisms arises from coordinated interactions amongst diverse cellular tissue populations. Existing approaches for long-term imaging of within-tissue circadian regulation remain low-throughput, highly specialized, and largely inaccessible. Here, we developed ClockCyte, a high-content fluorescent live-imaging platform that enables continuous monitoring of circadian rhythms in up to 144 brain tissue samples. Using the mouse suprachiasmatic nucleus as a model, ClockCyte captures the differential circadian tissue regulation of neurons and astrocytes. We further identified a previously uncharacterized oscillatory circadian compartment in axonal calcium, showing highly homogeneous activity, opposed to waves of intracellular neuronal calcium. By deleting Bmal1 in neurons, we reveal the network underpinnings connecting clock gene expression to network-wide axonal regulation. The discovery of distinct circadian properties of axonal calcium and their disruption by Bmal1 ablation highlights the potential to reveal new principles of intra-tissue network-level circadian organization. More broadly, this approach will enable systematic explorations of how cell-type-specific and compartmentalized subcellular rhythms contribute to brain physiology.
    Keywords:  brain tissue; circadian rhythms; live‐imaging
    DOI:  https://doi.org/10.1002/advs.75427
  15. Nat Rev Drug Discov. 2026 Apr 28.
    AhR inhibition promotes axon regeneration.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-026-00072-y
  16. QRB Discov. 2026 ;7 e3
    Electrochemical measurements at human iPSC-derived FOXA2 dopaminergic neurons suggest a role for partial release in presynaptic plasticity.
    Chaoyi Gu, Alicia Lork, Soodabeh Majdi, Stefania Rabasco, Huashan Peng, Anjie Ni, Carl Ernst, Andrew G Ewing.
      During the past decade, emerging studies using electrochemistry and nanoscale imaging have demonstrated that partial exocytotic release is prevailing in neuroendocrine cell models. However, due to complicated structure and culture process, few studies have been carried out using neurons, especially human neurons. Here, dopamine (DA) release from individual vesicles and DA content stored within vesicles were quantified from induced pluripotent stem cell-derived DA neurons with electrochemical techniques. The results indicate that around 61% of the total vesicular DA content is released from these neurons during exocytosis. The vesicular content quantified in DA neurons is significantly higher than that in undifferentiated neural progenitor cells, owing to the increased appearance of dense-core vesicles that are able to store more DA molecules than the clear vesicles. When the neurons are differentiated with BAY-K8644, which stimulates neuronal maturation as well as DA release, the release fraction rises to 91%. The use of BAY-K8644 can be considered as chronic stimulation and leads to similar effects on exocytosis as repetitive stimulation, which triggers short-term plasticity. This study demonstrates partial release in DA transmission in human neurons and provides a link between neuronal maturation and the formation of plasticity. Furthermore, this work suggests that the fraction of release in exocytosis at human neurons may be a factor in determining plasticity.
    Keywords:  dopamine signaling; electrochemistry; neuron; partial release; plasticity
    DOI:  https://doi.org/10.1017/qrd.2026.10019
  17. Acta Physiol (Oxf). 2026 Jun;242(6): e70230
    The Recycling Endosomal (Na+, K+)/H+ Exchanger NHE6/SLC9A6 Facilitates Signal Transduction by Shuttling Cyclin-Dependent Kinase 5 to the Plasma Membrane.
    Rebecca Flessner, Alina Ilie, Léo Han, Annie Boucher, Rebecca Anne McKinney, Reza Sharif-Naeini, John Orlowski.
       AIM: The alkali cation/proton exchanger NHE6/SLC9A6 regulates luminal pH homeostasis and trafficking of recycling endosomes in most tissues, especially neurons. Loss-of-function mutations in NHE6 cause Christianson Syndrome, an X-linked neurodevelopmental and neurodegenerative disorder; however, the underlying molecular and cellular mechanisms remain unclear. Here, we describe a new role for NHE6 as a scaffolding platform for recruiting and delivering signaling molecules to the plasma membrane.
    METHODS: The yeast two-hybrid system was used to screen a human brain cDNA library for proteins that bind to the cytoplasmic C-terminus of NHE6.
    RESULTS: Cyclin-dependent kinase 5 (CDK5) was identified as a putative interacting partner. CDK5 is widely expressed and phosphorylates diverse proteins involved in vital processes, including receptor signaling, cytoskeletal organization, endocytosis, exocytosis, and apoptosis. Formation of a NHE6/CDK5 complex was confirmed by biochemical assays and microscopy using Chinese hamster ovary AP-1 and human neuroblastoma SH-SY5Y cells. CDK5, in a complex with its activator subunit p35/CDK5R1, did not directly phosphorylate or regulate the membrane trafficking of NHE6. By contrast, NHE6 expression enhanced the localization of CDK5 and p35 to endosomal- and plasmalemmal-enriched membrane fractions and elevated cell surface accumulation of the CDK5-regulated transient receptor potential V1 (TRPV1) cation channel.
    CONCLUSIONS: These data indicate that NHE6, aside from its main pH-regulatory function, can act concomitantly as a scaffold for recruitment of CDK5/p35 to endosomes and the plasma membrane where the kinase is now primed to activate neighboring effectors important for cell function.
    Keywords:  alkali cation/proton exchanger; cyclin‐dependent kinase 5; endosomes; mammalian; protein trafficking; serine/threonine protein kinase; yeast two‐hybrid assay
    DOI:  https://doi.org/10.1111/apha.70230
  18. Toxins (Basel). 2026 Apr 15. pii: 186. [Epub ahead of print]18(4):
    Interference of Large Clostridial Glucosyltransferases with the Endolysosomal Pathway: Toxin-Induced Imbalance of Early Endosomes, Functional Lysosomes and Autophagosomes.
    Anna Langejürgen, Gudula Schmidt, Leon Unsöld, Helma Tatge, Ethel Oyson, Ralf Gerhard.
      Toxin A and B from Clostridioides difficile are the main pathogenicity factors for clinical symptoms of C. difficile infections. Receptor-mediated endocytosis and endosomal escape are required for targeting substrate proteins of the Rho-GTPase family. We previously reported that Toxin B (TcdB) affects endo-lysosomal transport and autophagic flux of target cells. These effects are independent from pathogenic Rho inhibition. Here, we aimed at further characterization of this event by immunofluorescent characterization of the vesicular structures that are affected. We found large aggregates of damaged endolysosomal structures positive for EEA1, LAMP1, CHMP4B and TcdB, as well as an increase in perinuclear concentration of non-mature autophagosomes (amphisomes) positive for SQSTM, Rab7, and LC3B. We investigated whether Rab7, a regulator of late endosome transport, is causative for decreased lysosome function. Although TcdB induced an increase in active Rab7, as tested by an RILP pull-down assay, inhibition of Rab7 did not prevent TcdB-induced decrease in cathepsin D as a surrogate for lysosome dysfunction. It also indicates that the observed increase in Rab7 positive amphisomes is secondary to lysosomal dysfunction. By applying an autoproteolytic deficient mutant of TcdB we proved that the release of the glucosyltransferase domain is mandatory for triggering all of these effects. This suggests that after membrane perforation the toxin remnants leave an open leak in endolysosomes affecting ion homeostasis. Investigation of all large clostridial glucosyltransferases and other toxins revealed lysosomal dysfunction as a general effect of many but not of all toxins that integrate into the endosome membrane.
    Keywords:  Clostridioides difficile toxins; Rab7; endosome; lysosome; pore formation; transcription factor EB
    DOI:  https://doi.org/10.3390/toxins18040186
  19. FEBS J. 2026 Apr 27.
    Iloperidone treatment mitigates the Juvenile Huntington's Disease phenotype possibly via Sigma-1 Receptor Modulation.
    Ersilia Fornetti, Gaia Galluzzi, Mario Frezzini, Cécile Exertier, Vittorio Brufani, Gianni Colotti, Giancarlo Ruocco, Jessica Rosati, Angelo Luigi Vescovi, Daniele Narzi, Ilaria Genovese, Andrea Ilari.
      Juvenile Huntington's disease (jHD) is a severe genetic disorder with combined neurodegenerative and neurodevelopmental features, characterized by early onset and markedly reduced life expectancy. Despite extensive efforts, drug development has been largely unsuccessful and no effective therapy capable of mitigating the pathological phenotype is currently available. Here, we investigated the potential of the FDA-approved drug iloperidone to ameliorate disease-related phenotypes in cortical neurons differentiated from patient-derived induced pluripotent stem cells. Given previous reports indicating that iloperidone can bind the Sigma 1 Receptor (S1R), we hypothesized that activation of S1R-dependent proteostasis pathways could contribute to its potential therapeutic effects. Treatment with iloperidone in this human-relevant model led to enhanced clearance of protein aggregates, improved neuronal survival, and activation of an adaptive unfolded protein response, consistent with engagement of proteostasis mechanisms. To test the hypothesis of S1R involvement and clarify the underlying molecular mechanisms, we combined cellular experiments with molecular dynamics simulations of S1R in its apo and ligand-bound states and in vitro mass photometry experiments comparing iloperidone with PD144418, a well-established antagonist. The simulations revealed distinct receptor conformations depending on the bound ligand: iloperidone induced specific conformational changes, whereas PD144418 behaved similarly to the apo receptor. Consistently, the two ligands exerted opposite effects on S1R oligomerization in vitro. Overall, the integration of experimental and computational data supports a model in which iloperidone behaves as an S1R agonist, promoting receptor dissociation and phenotypic recovery through modulation of proteostasis.
    Keywords:  Juvenile Huntington's disease; S1R induced oligomerization; iloperidone; induced pluripotent stem cell‐derived neurons; proteostasis/unfolded protein response; sigma‐1 receptor (S1R)
    DOI:  https://doi.org/10.1111/febs.70563
  20. bioRxiv. 2026 Feb 24. pii: 2026.02.23.707492. [Epub ahead of print]
    Statins and genetic inhibition of the mevalonate pathway activate an ATF3-STMN2 regenerative program.
    Matthew Nolan, Sandeep Aryal, I Sandra Ndayambaje, Maize Cao, Peyton Lee, Moriah Hovde, Shuqi Yun, Josette Wlaschin, Aaron Held, Hortense Beaussant, Benjamin Wymann, Chao Zong-Lee, Su Min Lim, Xin Jiang, Nandini Ramesh, Ana Rita Agra Almeida Quadros, Ayub Boulos, Nicolas Zinter, Shireen Salem, Laïla El-Tayar, Melinda Beccari, Maximiliano Presa, Charles Jourdan Ferreras Reyes, Yin Yin Ruan, Grant Griesman, Corey Aguilar, James Hawrot, Hayden Wheeler, Zevik Melamed, Benjamin P Kleinstiver, Mark Albers, Don W Cleveland, Rudolph E Tanzi, Cathleen M Lutz, Robert D Hubbard, Dione Kobayashi, Michael Ward, Christiano R R Alves, Brian Wainger, Claire Le Pichon, Clotilde Lagier-Tourenne.
      Loss of neuronal regenerative capacity is a common feature of neurodegenerative disease and axonal injury, yet the transcriptional programs governing this state remain poorly defined. Stathmin-2 (STMN2), a tubulin-binding protein essential for axon maintenance and repair, is profoundly depleted following loss of nuclear TDP-43 in neurodegenerative disease. Here, we identify statins as potent inducers of STMN2 expression. Pharmacological and genetic suppression of the mevalonate pathway, and subsequent prevention of protein geranylgeranylation, restored STMN2 levels in TDP-43 deficient cells and promoted neurite growth. STMN2 induction was abrogated when using a statin analogue unable to interact with HMG-CoA reductase, and through co-administration of mevalonate or geranylgeranyl diphosphate substrates. RNA-seq revealed that statins induce a coordinated pro-regenerative transcriptional response, including activation of the AP-1 transcription factor complex gene, ATF3 . Loss of ATF3 attenuated STMN2 induction in vitro , and diminished injury-induced Stmn2 upregulation in spinal motor neurons in vivo . These results demonstrate statins as modulators of ATF3 and STMN2 expression and highlight their therapeutic potential in neurodegenerative disease.
    DOI:  https://doi.org/10.64898/2026.02.23.707492
  21. Nucleic Acids Res. 2026 Apr 23. pii: gkag233. [Epub ahead of print]54(8):
    Mitochondrial DNA replication is regulated by endoplasmic reticulum-mitochondrial contact sites, the mitochondrial calcium uniporter, and manganese.
    Amaia Lopez de Arbina, Angelica Zamudio-Ochoa, Mikel Muñoz-Oreja, Diego Perez-Rodriguez, Laura Mosqueira-Martín, Rebecca Lasalandra, Marina Villar-Fernandez, Uxoa Fernandez-Pelayo, Laura Rodriguez-Gomez, Seungtae Lee, Francisco Gil-Bea, Nerea Osinalde, Ainara Vallejo-Illaramendi, Dmitry Temiakov, Antonella Spinazzola, Ian J Holt.
      Mitochondrial DNA replication occurs at contact sites between the endoplasmic reticulum (ER) and mitochondria (ERMCS). Beyond the known role of the tubular ER protein RTN4, the factors regulating this process are poorly defined. Here, we show that repressing the ER protein ERLIN2 in human fibroblasts depletes ER-mitochondrial contact sites and inhibits mitochondrial DNA replication, as does silencing RTN4 or the ER-mitochondrial tether GRP75. GRP75 or RTN4 scarcity also decreases the level of the mitochondrial calcium uniporter (MCU), whose inhibition blocks mitochondrial DNA synthesis. Because ERMCS depletion did not diminish mitochondrial calcium, and MCU complex can transport manganese, we tested whether manganese could bypass these defects. Manganese supplementation restored mitochondrial DNA replication in cells lacking ERMCS or with inhibited MCU, identifying manganese as a critical mediator. We then considered mitochondrial transcription as a potential manganese target, since it provides both transcripts for gene expression and primers for DNA replication. In vitro, manganese inhibits transcription re-start and stimulates RNA synthesis at the light-strand origin of replication. These findings support a model in which ER-mitochondrial contact sites, in conjunction with MCU, deliver manganese from the ER to mitochondria to promote DNA replication, potentially by modulating mitochondrial RNA polymerase activity.
    DOI:  https://doi.org/10.1093/nar/gkag233
  22. STAR Protoc. 2026 Apr 28. pii: S2666-1667(26)00185-1. [Epub ahead of print]7(2): 104532
    Protocol for culture and maintenance of canine induced pluripotent stem cells.
    Kohei Shishida, Masaya Tsukamoto, Toshiya Nishimura, Shingo Hatoya.
      Here, we present a protocol for a feeder-free culture system for canine induced pluripotent stem cells (ciPSCs) using a recently developed medium, termed AR medium, on extracellular matrix (ECM)-coated dishes. We describe steps for thawing frozen ciPSC stocks, medium exchange, passaging, and cryopreservation. This technique enables stable colony formation, high viability, and consistent proliferation of ciPSCs during long-term maintenance. It provides a reproducible platform for downstream applications of ciPSCs, such as cell differentiation, gene editing, and disease modeling. For complete details on the use and execution of this protocol, please refer to Nishimura et al.1.
    Keywords:  Cell Biology; Developmental biology; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2026.104532
  23. bioRxiv. 2026 Apr 13. pii: 2026.04.10.717788. [Epub ahead of print]
    Sorcin couples Annexin A11 recruitment and ESCRT-III assembly during plasma membrane repair.
    Jordan Matthew Ngo, Justin Krish Williams, Abinayaa Murugupandiyan, Randy Schekman.
      The absence of a cell wall affords animal cells diverse functionality at the cost of acute sensitization to plasma membrane (PM) damage. Thus, animal cells tightly monitor and maintain the integrity of their PM to prevent cell death. Genetic loss of PM repair factors is associated with human diseases including muscular dystrophy and neurodegeneration. Despite evidence that annexin and endosomal sorting complex required for transport (ESCRT) proteins are required for PM repair, the extent to which their recruitment is coordinated at sites of membrane damage is unclear. Here, we identify sorcin as a new PM repair factor that directly couples annexin A11 (ANXA11)-mediated sensing of PM damage and ESCRT-III assembly. We demonstrate that ANXA11, recruited to the PM upon damage-induced calcium influx, serves as an anchor that facilitates the sequential recruitment of sorcin and ESCRT-III at PM lesions. Our data highlight mechanistic and topological similarities between the budding of membrane-enveloped viruses and damage-induced microvesicles. We propose that they share a common mechanism of membrane budding and speculate that membrane-enveloped viruses may have co-opted this host pathway of PM ESCRT recruitment to facilitate virion assembly and propagation.
    DOI:  https://doi.org/10.64898/2026.04.10.717788
  24. bioRxiv. 2026 Apr 17. pii: 2026.04.15.718713. [Epub ahead of print]
    Developmental regulation of kinetochore phosphorylation determines mitotic fidelity.
    Brian Galaviz Sarmiento, Duane A Compton, Kristina M Godek.
      Accurate chromosome segregation relies on proper centromere and kinetochore formation and phospho-regulation. We previously demonstrated that a pluripotent state confers a low fidelity of chromosome segregation, however it is unknown how a pluripotent state impacts centromere and kinetochore function. Here, we demonstrate that both centromere and kinetochore structural organization and phosphorylation in mitosis are developmentally regulated. CENP-A, CENP-C, and HEC1 protein abundance is reduced at mitotic centromeres and kinetochores of human pluripotent stem cells (hPSCs) compared to isogenic somatic cells; however, elevating their levels does not improve chromosome segregation fidelity. Rather, we find that reduced phosphorylation of kinetochores is responsible for their low fidelity. HEC1 is hypophosphorylated at kinetochores of hPSCs compared to isogenic somatic cells at Cyclin B/Cdk1 and Aurora kinase phospho-sites. Inhibiting PP2A phosphatase activity or differentiation increases HEC1 phosphorylation at hPSC kinetochores decreasing chromosome segregation errors. Thus, mitotic fidelity in non-transformed human cells depends on the developmental regulation of the kinase and phosphatase networks controlling kinetochore phosphorylation.
    Summary: Galaviz Sarmiento et al show that the developmental regulation of kinetochore phosphorylation governs mitotic fidelity. HEC1 is hypophosphorylated at kinetochores of hPSCs during mitosis contributing to their high rate of chromosome segregation errors. While differentiation increases HEC1 phosphorylation improving chromosome segregation fidelity.
    DOI:  https://doi.org/10.64898/2026.04.15.718713
  25. STAR Protoc. 2026 Apr 27. pii: S2666-1667(26)00177-2. [Epub ahead of print]7(2): 104524
    Protocol for generating iPSC-derived intestinal organoids through dissection to model cystic fibrosis therapies.
    Alexander J Stuffer, Barbara Tabak, Joshua Conte, Victoria Momyer, Mercy Chado, Matthew Armstrong, Phillip Wible, Andrey Sivachenko, Normand Allaire, Junjie Lu, Martin Mense, John E Mahoney.
      Intestinal organoids (IOs) are versatile, physiologically relevant models of the human gut. In cystic fibrosis research, IOs help evaluate CFTR correctors, potentiators, and translational readthrough compounds. Here, we present a protocol for generating induced pluripotent stem cell (iPSC)-derived IOs with high phenotypic similarity to primary material. We describe steps for establishing iPSC culture, generating intestinal progenitors via directed differentiation, and maturing these intestinal progenitors using three-dimensional culture. We then detail procedures for establishing intestinal organoid cultures from these progenitors using dissection-based techniques.
    Keywords:  Cell Differentiation; Cell culture; Cell-based Assays; Organoids
    DOI:  https://doi.org/10.1016/j.xpro.2026.104524
  26. Front Cell Dev Biol. 2026 ;14 1776289
    Autophagy: mechanisms, roles in human diseases, and therapeutic perspectives.
    Jiazhen He, Teng Qi.
      Autophagy, a conserved intracellular degradation and recycling process, maintains cellular homeostasis by eliminating damaged organelles, misfolded proteins, and invading pathogens. Dysregulation of autophagy either excessive or insufficient contributes to the pathogenesis of numerous human diseases, spanning the respiratory, locomotor, circulatory, digestive, urinary, and nervous systems, as well as cancer. This Mini Review summarizes the core mechanisms and classification of autophagy, highlights its dual roles in various pathological conditions, discusses existing controversies and research gaps, and outlines potential future directions for therapeutic targeting. A concise overview of key findings provides readers with an updated understanding of autophagy's multifaceted functions in disease development and treatment.
    Keywords:  autophagy; cancer; chaperone-mediated autophagy; human diseases; macroautophagy; mitophagy; neurodegenerative disorders; therapeutic targeting
    DOI:  https://doi.org/10.3389/fcell.2026.1776289
  27. Cell Physiol Biochem. 2026 Apr 06. 60(2): 136-174
    mTOR Signalling in Neurodegenerative Disorders: Unveiling Key Factors, Mechanistic Insights, and Possible Therapeutic Interventions.
    Niraj Kumar Jha, Payal Chauhan, Mosleh Mohammad Abomughaid, D Avinash, Abdulmajeed G Almutary, Sorabh Lakhanpal, Ajay Singh, Ghassan M Sulaimani, Hayder M Al-Kuraishy, Hamdoon A Mohammed, Jyotsna Misra, Kunal Thakur, Dhruv Kumar.
      Neurodegenerative diseases (NDDs) are defined by the gradual degeneration of neuronal cells, wherein the accumulation of misfolded proteins can lead to memory impairments, motor dysfunctions, and other deteriorations. Despite the widespread impact, there are currently no viable pharmaceuticals to treat these disorders. The mTOR protein is a crucial regulator of cell survival, growth, autophagy, and apoptosis. Targeted modulation of mTOR signaling holds promise for mitigating neurodegeneration in Alzheimer's, Huntington's, ALS, and Parkinson's disease. Understanding its interactions with pathways such as PI3K/Akt, AMPK, and SIRT1 is essential for developing effective therapeutics.
    Keywords:  mTOR ; Brain ; Neurodegeneration ; Autophagy ; Apoptosis ; Therapeutics
    DOI:  https://doi.org/10.33594/000000858
  28. Brain Commun. 2026 ;8(2): fcag127
    Individualized phenotyping of functional amyotrophic lateral sclerosis pathology in sensorimotor cortex.
    Avinash Kalyani, Alicia Northall, Stefanie Schreiber, Jascha Brüggemann, Stefan Vielhaber, Marwa Al Dubai, Abrar Bin Ramadan, Hendrik Mattern, Oliver Speck, Christoph Reichert, Esther Kuehn.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons in primary motor cortex, leading to muscle weakness, atrophy and death within a median of 3 years. Even though ALS is characterized by different disease subtypes affecting different body parts, individualized phenotyping of functional ALS pathology has so far not been achieved. We recorded 7 Tesla functional MRI data while ALS patients and matched controls moved affected and non-affected body parts in the MR scanner. We applied robust Shared Response Modelling for capturing ALS-specific shared responses for group classification, and Partial Least Squares regression for relating the latent variables to clinical subtypes and the degree of disease progression. We show that disease onset and severity can be best modelled by functional connectivity rather than local activation changes. We also show that functional disease-defining information in primary motor cortex is not the strongest in the area that is behaviourally first-affected, deviating from the behavioural phenotype of the patients. When computing the model's weight distribution of the King stage classification and projecting them back into voxel space, the highest mean weights are present in the foot and tongue/face regions. Our data highlight the importance of 7 Tesla functional MRI task-based functional connectivity measures for classifying ALS patients in addition to structural readouts and provides evidence that a 7 Tesla functional MRI can be used for identifying a disease signature of each individual ALS patient.
    Keywords:  7T-fMRI; PLSR; amyotrophic lateral sclerosis; disease progression; sensorimotor cortex
    DOI:  https://doi.org/10.1093/braincomms/fcag127
  29. Turk J Biol. 2026 ;50(2): 158-169
    Modulating microtubule stability via α-tubulin acetylation partially restores Golgi fragmentation in spinal muscular atrophy.
    Pelin Zobaroğlu Özer, Memet Gözüböyük, Özge Çetin, Niko Hensel, Güzin Emecen, Adam Malik, Melissa Bowerman, Peter Claus, Hayat Erdem Yurter, Gamze Bora Akoğlu.
       Background/aim: Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by the loss of survival of motor neuron (SMN) protein. SMN deficiency leads to perturbations of the cytoskeleton, including microtubules, which are mainly involved in motility-related cellular processes. However, the molecular mechanisms of microtubule dysregulation in SMA remain elusive. Alpha (α)-tubulin is a structural component of microtubules, and its posttranslational modifications affect microtubule dynamics. Here, we aimed to investigate α-tubulin acetylation and related molecular mechanisms in SMA.
    Materials and methods: Two different SMA mouse models, the Drosophila melanogaster model and patient-derived fibroblasts, were used in the study. Western blot and quantitative microscopic analysis were performed to analyze α-tubulin acetylation and related mechanisms.
    Results: The acetylation level of α-tubulin was decreased in the Drosophila model and in SMA patient fibroblast cells but not in mouse models. This decrease in acetylation is associated with upregulation of the major tubulin deacetylase, HDAC6, in patient cells compared with healthy controls. Microtubules play a role in the organization of the Golgi apparatus, and we demonstrated that increasing α-tubulin acetylation by pharmacological inhibition of HDAC6 partially restored the fragmented morphology of the Golgi apparatus in SMA.
    Conclusion: Our findings provide new insight into the molecular basis of SMA, indicating that cellular pathologies, including abnormal Golgi morphology, are associated with microtubule dysregulations caused by altered α-tubulin posttranslational modifications and regulatory proteins. Our findings support that microtubule perturbations are part of SMA pathology.
    Keywords:  Golgi fragmentation; HDAC6; Spinal muscular atrophy; α-tubulin acetylation
    DOI:  https://doi.org/10.55730/1300-0152.2798
  30. Cells. 2026 Apr 17. pii: 712. [Epub ahead of print]15(8):
    An Inducible hiPSC-Derived Human Podocyte Model for Functional Analysis of TRPC6 Variants Associated with FSGS.
    Lilas Batool, Krithika Hariharan, Gabriel Stölting, Tingting Zhong, Dimitry Tsvetkov, Manfred Gossen, Andreas Kurtz.
      Podocyte injury is a characteristic feature of focal segmental glomerulosclerosis (FSGS) that leads to the development of nephrosis as its loss causes proteinuria and progressive glomerulosclerosis. The physiological function of podocytes is critically dependent on proper intracellular calcium levels; an excess or shortage of calcium influx in these cells may result in foot process effacement, apoptosis, and nephron degeneration. A key protein responsible for the regulation of calcium flux is the canonical transient receptor potential 6 (TRPC6) expressed in podocytes. Several mutations in the TRPC6 gene have been associated with FSGS. Here we present a systematically optimized inducible FSGS model system in human induced pluripotent stem cells (hiPSCs). We generated and phenotypically characterized three transgenic hiPSC lines with regulatable overexpression of TRPC6 wild-type and FSGS-associated gain-of-function (GoF, P112Q) and loss-of-function (LoF, G757D) mutations. Moreover, these cell lines were differentiated into induced podocytes (ipodocytes). We assessed the impact of TRPC6 GoF and LoF mutants on calcium influx in combination with TRPC6 agonists and antagonists. Our data showed relative calcium responses consistent with the GoF and LoF phenotypes. Transgenic iPSC-based models, like the one presented here, are instrumental to studying disease mechanisms in vitro and investigating the outcomes of, and possible therapeutic interventions for, this complex disease.
    Keywords:  FSGS; TRPC6; hiPSC; podocytes
    DOI:  https://doi.org/10.3390/cells15080712
  31. Gene. 2026 Apr 25. pii: S0378-1119(26)00198-8. [Epub ahead of print] 150188
    The interaction between exercise and autophagic flux in neurodegenerative muscle loss.
    Dongdong Wang, Yahui Li.
      Neurodegenerative diseases are increasingly recognized as systemic disorders that extend beyond the central nervous system and profoundly affect skeletal muscle. Muscle weakness and atrophy in these conditions are driven not only by denervation but also by mitochondrial dysfunction, chronic inflammation, and impaired proteostasis. Among the mechanisms underlying muscle deterioration, autophagy has emerged as a critical regulator of cellular quality control. Balanced autophagic flux is essential for the removal of damaged proteins and dysfunctional mitochondria, thereby preserving metabolic homeostasis and neuromuscular junction stability. Conversely, dysregulated autophagy contributes to proteotoxic stress and accelerates muscle degeneration in neurodegenerative disorders. Exercise is a potent physiological stimulus capable of modulating autophagy in skeletal muscle. Preclinical models and emerging clinical evidence indicate that appropriately prescribed exercise can restore impaired autophagic flux, enhance mitochondrial quality control, and improve muscle function in neurodegenerative and aging-related muscle loss. However, the effects of exercise are context- and intensity-dependent, underscoring the need for individualized therapeutic strategies. This review synthesizes current evidence on the interaction between exercise and autophagic regulation in neurodegenerative muscle loss. Exercise as a therapeutic strategy is supported by well-defined molecular and cellular mechanisms, including the regulation of autophagy and mitochondrial quality control.
    Keywords:  Autophagic flux; Exercise; Neurodegenerative diseases; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.gene.2026.150188
  32. Front Biosci (Landmark Ed). 2026 Apr 14. 31(4): 47914
    Computational Pathology as a Mechanistic Discipline: From Morphology to Molecular Data.
    Nicola Fusco, Konstantinos Venetis.
      Pathology is undergoing a shift from morpho-molecular interpretation toward the computational integration of molecular mechanisms encoded in tissue architecture. Here, we argue that such morphology-driven molecular inference may enable biomarker prediction and potentially generate therapeutic insights directly from routine histology. This paradigm has important clinical implications for quantitative biomarker testing, patient stratification, and the design of digital biomarker-based clinical trials. At the same time, we emphasize that most current artificial intelligence (AI) models remain correlative, with clinical impact still dependent on rigorous validation, integration into workflows, and ethical governance. Addressing these open challenges will be essential for computational pathology to mature into a clinically meaningful discipline.
    Keywords:  artificial intelligence; biomarkers; deep learning; pathology
    DOI:  https://doi.org/10.31083/FBL47914
  33. Nat Commun. 2026 Apr 27. pii: 3654. [Epub ahead of print]17(1):
    Quantitative live imaging reveals PRICKLE1 controls junctional neural tube morphogenesis independent of Planar Cell Polarity.
    Jian Xiong Wang, Yanina D Alvarez, Siew Zhuan Tan, Samara N Ranie, Samantha J Stehbens, Melanie D White.
      Neurulation, the process that forms the neural tube - the precursor to the brain and spinal cord - is frequently disrupted in congenital malformations. Primary and secondary neurulation are integrated at a junctional zone, yet the cellular dynamics linking these programs remain unknown. Using high-resolution quantitative live imaging in transgenic quail embryos, we show that the junctional neural tube forms through two coordinated processes: mediolateral convergence and EMT-driven ingression of medial neuroepithelial cells. We demonstrate that PRICKLE1, a core PCP protein, orchestrates these behaviors independently of planar polarity cues. PK1 is enriched at the apical cortex of medial cells, where it drives actomyosin accumulation and apical constriction. This function is essential for both convergence and cell ingression but is uncoupled from classical PCP axis establishment. Our findings redefine the molecular basis of junctional neurulation and implicate impaired EMT as a central cause of localized neural tube defects.
    DOI:  https://doi.org/10.1038/s41467-026-71242-0
  34. bioRxiv. 2026 Apr 17. pii: 2026.04.16.719038. [Epub ahead of print]
    Lipids Regulate Export of Lysosomal Enzymes from the Endoplasmic Reticulum.
    Baolong Xia, Myeonghoon Han, Isaac Park, Norbert Perrimon.
      Lysosomal enzymes are synthesized in the Endoplasmic Reticulum (ER) and transported to lysosomes to execute their functions. Deficiencies in lysosomal enzymes or components of the lysosomal transport machinery result in lysosomal storage disorders. While mannose-6-phosphate mediated lysosomal enzymes sorting in the Golgi has been extensively characterized, the mechanisms governing their export from the ER remain elusive. Here, we show that de novo lipogenesis, a metabolic pathway responsible for fatty acid synthesis, regulates lysosomal enzyme transport. Inhibition of de novo lipogenesis leads to the retention of lysosomal enzymes within the ER. Mechanistically, fatty acid derived from de novo lipogenesis is used for Arf1 myristoylation. Myristoylated Arf1 promotes retrograde vesicle trafficking from the Golgi to the ER, thereby maintaining the homeostatic bidirectional flux required for efficient ER export of lysosomal enzymes. Our findings uncover a critical functional link between lipid metabolism and lysosomal enzyme trafficking.
    DOI:  https://doi.org/10.64898/2026.04.16.719038
  35. Mol Brain. 2026 Apr 26. pii: 32. [Epub ahead of print]19(1):
    Impaired phrenic nerve axon development and diaphragm neuromuscular junction formation in embryonic Cyfip2-null mice.
    Su Yeon Kim, Jun Young Oh, U Suk Kim, Ruiying Ma, Yoonhee Kim, Kihoon Han.
      Pathogenic variants in CYFIP2 cause developmental and epileptic encephalopathy 65 (DEE65) and have been predominantly investigated in the context of central nervous system dysfunction. However, emerging clinical evidence suggests that peripheral nervous system (PNS) involvement may also contribute to disease manifestations. To explore this possibility, we examined the role of CYFIP2 in the development of the phrenic neuromuscular system, which is essential for neonatal respiration. Because conventional Cyfip2-null (Cyfip2-/-) mice exhibit perinatal lethality, we analyzed phrenic nerve axon development and diaphragm neuromuscular junction (NMJ) formation in embryonic mice. At embryonic day 16.5, Cyfip2-/- embryos displayed significantly reduced phrenic nerve axon length and branching compared to wild-type controls. Postsynaptic acetylcholine receptor (AChR) clustering in Cyfip2-/- diaphragms showed spatial heterogeneity: sparse regions exhibited a significant increase in endplate bandwidth, whereas dense regions showed a decreasing trend. Further analysis using synaptophysin and α-bungarotoxin labeling revealed reduced pre- and post-synaptic puncta density and decreased colocalization, despite preserved puncta intensity and volume, indicating impaired synaptic organization. Together, these findings demonstrate that CYFIP2 is required for proper phrenic nerve innervation and NMJ organization during embryonic development. This study extends the functional scope of CYFIP2 to the PNS and establishes the diaphragm as a tractable model for investigating peripheral mechanisms underlying CYFIP2-associated neurodevelopmental disorders.
    Keywords:  Axon; CYFIP2; Diaphragm; Embryo; Neuromuscular junction; Phrenic nerve
    DOI:  https://doi.org/10.1186/s13041-026-01301-6
  36. bioRxiv. 2026 Apr 17. pii: 2026.04.16.717704. [Epub ahead of print]
    A robust workflow for 3D imaging of human mitochondria using cryo-electron tomography.
    Akhil Gargey Iragavarapu, Oleg Artemchuk, Daija Bobe, Anna C Ratliff, Evgeny Pavlov, Halil Aydin.
      Mitochondria are dynamic signaling organelles that transduce metabolic and biochemical cues to facilitate cellular adaptation. Their complex structure and dynamics are essential for integrating metabolic pathways, responding to stressors, and communicating inter- and intra-cellular signals. While optimal mitochondrial activity is frequently linked to cellular and organismal health-influencing processes ranging from metabolism and regulated cell death to differentiation and growth-the mechanistic links between mitochondrial dysfunction and cellular defects leading to human disease remain incompletely understood. Understanding how mitochondrial shape and function are linked is crucial for deciphering the regulatory mechanisms of cell survival and fate. Here, we present a molecular resolution cryo-electron tomography (cryo-ET) imaging and image analysis platform to investigate the structure of isolated human mitochondria under different conditions. We describe optimized protocols for isolating mitochondria from human cells, vitrifying these samples with high-pressure freezing (HPF) using the waffle method, cryo-focused ion beam (cryo-FIB) milling to generate thin sections (lamellae), and imaging with cryo-transmission electron microscopy (cryo-TEM). This is complemented by a robust downstream processing pipeline for tilt-series alignment, tomogram reconstruction, and three-dimensional (3D) segmentation of tomograms using the latest state-of-the-art algorithms. With some variations, this versatile workflow is adaptable to other subcellular compartments for structural studies in isolation or within intact cells. Furthermore, our protocols provide a critical foundation for investigating the in-situ structure of protein machineries that govern key cellular processes.
    DOI:  https://doi.org/10.64898/2026.04.16.717704
  37. Brain Sci. 2026 Apr 19. pii: 427. [Epub ahead of print]16(4):
    Brain Organoids: Emerging Platforms for Modern Neuroscience.
    Lian Wang, Liwei Mao, Qing Cao, Xuemei Zong.
      Brain organoids represent three-dimensional structures that allow for human-specific studies in brain development, pathology and therapeutics. These self-organizing systems, formed through the differentiation of human pluripotent stem cells, can mimic important cellular and molecular events of brain development and therefore serve as a platform for the investigation of neurodevelopmental and neurodegenerative diseases, brain injuries, and tumorigenesis. Although brain organoids show promising perspectives in the study of human physiology, existing brain organoid platforms are hindered by issues of under vascularization, immaturity and protocol variability. Nevertheless, the rapid development of new bioengineering, microfluidic and multi-omics tools and approaches allows us to overcome existing problems and increase the physiological significance of these organoids. Brain organoid transplantation and functional studies further enhance the applications of brain organoids in drug screening, disease modeling and personalized medicine. Here, we provide an overview of recent developments in the field of brain organoid cultures, functional characteristics and translational applications.
    Keywords:  3D culture systems; bioengineering; brain organoids; disease modeling; neural development; organoid transplantation
    DOI:  https://doi.org/10.3390/brainsci16040427
  38. Front Neurol. 2026 ;17 1790581
    Augmented and prematurely occurring H-reflex recovery curve shows enhanced spinal network excitability in ALS patients when employing the double stimulation paradigm.
    Sebastian A Wölk, Johannes Prudlo, Uwe Walter, Robert Patejdl.
      Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder in which motoneuron loss in the brain and spinal cord induces complex neuroplastic changes. Although these alterations hold considerable potential for clinical diagnosis and disease monitoring, they remain underutilized due to the lack of sensitive and non-invasive assessment methods. The H-reflex is a monosynaptic spinal reflex arc and represents the neurophysiological analog of the Achilles tendon reflex. A modified H-reflex double-stimulation paradigm enables differentiation of the temporal dynamics of spinal inhibitory and excitatory mechanisms. In ALS, this approach may provide clinically relevant insights into motor system dysfunction. Furthermore, this approach may contribute to a better understanding of the pathophysiology of spinal network plasticity associated with this disease, reflecting the complex interplay between spinal and supraspinal pathways. We assessed H-reflex recovery in 15 ALS patients and 82 non-ALS subjects, including 12 age-matched healthy controls (HC). The protocol included 14 interstimulus intervals (ISI) within a timeframe of up to one second. In contrast to the HCs, ALS patients exhibited recovery at ISIs of 30 or 50 ms. At interstimulus intervals ranging from 50 to 200 ms, the extent of recovery was significantly elevated in the ALS group compared to the age-matched HCs. ALS patients thus demonstrate heightened spinal network excitability as evidenced by an augmented and prematurely occurring H-reflex recovery measurement. These alterations likely reflect changes in neuronal network activity and can be attributed to modifications in both segmental spinal circuits and supraspinal regulatory pathways.
    Keywords:  H-reflex; H-reflex recovery curve; Renshaw cell; amyotrophic lateral sclerosis; corticospinal; electrodiagnosis; recurrent inhibition; spinal network excitability
    DOI:  https://doi.org/10.3389/fneur.2026.1790581
  39. Neuroscience. 2026 Apr 29. pii: S0306-4522(26)00285-X. [Epub ahead of print]
    From stability to pathology: protein degradation pathways underlying synaptic proteins in neurological diseases.
    Yuanyuan Li, Xiao-Yu Hou, Yanmei Tao.
      Synaptic function and plasticity depend on the precise control of protein abundance and turnover, governed by the balance of synthesis and degradation. This review examines the regulatory mechanisms that maintain synaptic protein stability, focusing on the Ubiquitin-Proteasome System (UPS), autophagy-lysosomal pathways, and related proteolytic systems. We detail how key enzymes, including E3 ligases such as Nedd4-1, Mdm2, and Parkin, and deubiquitinating enzymes like USP46 and USP8, dynamically regulate the degradation of critical synaptic components from AMPA and NMDA receptors to scaffolds like PSD-95 and SHANK3. We further explore how autophagy, including chaperone-mediated and activity-dependent forms, contributes to synaptic remodeling and quality control. Crucially, dysfunction of synaptic degradation pathways is a common thread in neurodevelopmental and neurodegenerative disorders. We summarize evidence linking proteostatic malfunction to the pathogenesis of Alzheimer's disease (through impaired clearance of Aβ and tau), Parkinson's disease (via α-synuclein turnover), epilepsy, autism spectrum disorder, and ischemic injury. The review highlights how genetic mutations in degradation machinery or their synaptic targets converge to disrupt synaptic integrity and neural circuit function. By integrating findings from basic neurobiology and disease models, this review underscores the central importance of synaptic proteostasis and aims to identify critical regulatory molecules that retain potentials for diagnostic biomarkers and therapeutic targets for neurological disease.
    Keywords:  Autophagy-lysosomal pathway; Neurological diseases; Synaptic protein stability; Ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.04.025
  40. J Neurosci. 2026 Apr 29. pii: e1675252026. [Epub ahead of print]46(17):
    Advances in Cell Therapy for Neural Repair.
    Lyandysha V Zholudeva, Soshana P Svendsen, Irene L Llorente, Vanessa Kan, Eve C Tsai, Victor Ogbolu, Liang Qiang, Edward D Wirth, Carlos A Paladini, Clive N Svendsen, Michael A Lane.
      Neural repair remains one of the foremost challenges in modern neuroscience, as damage to the central nervous system caused by injury or neurodegenerative disease often leads to irreversible loss of function. The advent and rapid evolution of utilizing stem cell biology have provided unprecedented opportunities to advance regenerative strategies aimed at restoring brain and spinal cord integrity, with the goal of regaining lost functions and improving outcomes for individuals living with injury and disease. Among these, cell therapies using derivatives of pluripotent stem cells have emerged as promising approaches, driving innovation from primary tissue transplants to the engineering of induced pluripotent stem cell-derived neuronal and glial progenitors and now to complex multicellular brain and spinal cord organoids. Complementing these biological innovations, artificial intelligence and machine learning are transforming regenerative neuroscience by enabling large-scale data analysis and predictive modeling. This review synthesizes recent progress across these areas, highlighting emerging technologies and therapeutic adjuncts that enhance the applicability and efficacy of neural repair paradigms.
    DOI:  https://doi.org/10.1523/JNEUROSCI.1675-25.2026
  41. NPJ Dement. 2026 ;2(1): 24
    Multi-omic phenotyping of MAPT V337M neurons reveals early changes in axonogenesis and tau phosphorylation.
    Gregory A Mohl, Gary Dixon, Emily Marzette, Justin McKetney, Avi J Samelson, Carlota Pereda Serras, Julianne Jin, Nabeela Ariqat, Andrea Keys, Cristian Chavira, Andrew Li, Steven C Boggess, Danielle L Swaney, Martin Kampmann.
      Tau aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia. There are disease-causing variants of the tau-encoding gene, MAPT, and the presence of tau aggregates is highly correlated with disease progression. However, the molecular mechanisms linking pathological tau to neuronal dysfunction are not well understood. This is in part due to an incomplete understanding of the normal functions of tau in development and aging, and how the associated molecular and cellular processes change in the context of causal disease variants of tau. To address these questions in an unbiased manner, we conducted multi-omic characterization of iPSC-derived neurons harboring the MAPT V337M mutation or MAPT knockdown. RNA-seq, ATAC-seq, and phosphoproteomics revealed that both the V337M mutation and tau knockdown perturbed levels of transcripts and phosphorylation of proteins related to axonogenesis or axon morphology. When we directly measured axonogenesis, we found that both MAPT V337M and MAPT knockdown caused decreased axon length. Surprisingly, we found that neurons with V337M tau had much lower tau phosphorylation than neurons with WT tau. CRISPR-based screens uncovered regulators of tau phosphorylation in neurons and found that factors involved in axonogenesis modified tau phosphorylation in both MAPT WT and MAPT V337M neurons. Intriguingly, the p38 MAPK pathway specifically modified tau phosphorylation in MAPT V337M neurons. We propose that V337M tau perturbs tau phosphorylation and axon morphology pathways that are relevant to the normal function of tau in development, which could contribute to previously reported cognitive changes in preclinical MAPT variant carriers.
    Keywords:  Cell biology; Molecular biology; Neurology; Neuroscience
    DOI:  https://doi.org/10.1038/s44400-026-00076-w
  42. Neurochem Res. 2026 Apr 27. pii: 145. [Epub ahead of print]51(3):
    FTDP-17T Mutations Promote Formation of Phosphorylated FTDP-17T TAU Oligomers That Cause Degeneration of Dopaminergic and Hippocampal Neurons via Activating ER Stress and Mitochondrial Pro-apoptotic Cascades.
    Hung-Li Wang, Yi-Hsin Weng, Ching-Chi Chiu, Wan-Shia Chen, Shu-Yu Liu, Tu-Hsueh Yeh.
      Heterozygous missense mutations of TAU cause frontotemporal dementia with parkinsonism linked to chromosome 17 with tau pathology (FTDP-17T). FTDP-17T neurodegeneration of hippocampal and substantia nigra dopaminergic cells causes dementia and parkinsonism motor deficits. FTDP-17T cellular model of mutant TAU-expressing differentiated dopaminergic or hippocampal neurons was utilized to test hypothesis that FTDP-17T (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs located in different domains of TAU cause neurodegeneration with the same pathomechanism. (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs caused degeneration of dopaminergic or hippocampal neurons via mutation-induced gain-of-neurotoxicity. (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) mutations promoted Ser202/Ser396/Ser404 phosphorylations of TAU and formation of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers in dopaminergic or hippocampal neurons. GSK-3β inhibitor AR-A014418 completely blocked (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs-induced neurotoxicity by preventing (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) mutations-augmented Ser202/Ser396/Ser404 phosphorylations and genesis of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers. Phospho-(R5H), phospho-(N279K), phospho-(K298E), phospho-(P301S), phospho-(K317M) or phospho-(G389R) TAUSer202/Ser396/Ser404 oligomers were found in ER of dopaminergic or hippocampal neurons and activated ER stress, UPR and ER stress apoptotic signaling. Overexpression of mitochondrial phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers caused mitochondrial malfunction via depolarizing mitochondrial membrane potential and oxidative damage by increasing ROS. Phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers-evoked upregulation of Noxa, Bim or Puma and mitochondrial defect and oxidative stress excited mitochondrial pro-apoptotic pathway. Our results suggest that shared pathomechanism underlying FTDP-17T (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs-induced neurotoxicity is mutation-augmented GSK-3β-mediated Ser202/Ser396/Ser404 phosphorylations and generation of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers, which cause neurodegeneration by stimulating ER stress and mitochondrial pro-apoptotic cascades.
    Keywords:  Dopaminergic neurons; FTDP-17T; FTDP-17T TAU; GSK-3β; Hippocampal neurons; Ser202/Ser396/Ser404 phosphorylations of TAU
    DOI:  https://doi.org/10.1007/s11064-026-04761-3
  43. bioRxiv. 2026 Apr 17. pii: 2026.04.14.717551. [Epub ahead of print]
    The exocyst is an insulin-sensitive regulator of amyloid precursor protein trafficking and amyloid-beta generation in neurons.
    Chantell Balaan, Geetika Y Patwardhan, Rachel K Sachs, Hanna Kumasaka, Swasthita Sadagopan, Shion Aou, Amanda J Lee, Luke T Nelson, Brian E Hew, Jesse B Owens, Noemi Polgar, Michael A Ortega, Robert A Nichols, Ben Fogelgren.
      Intracellular trafficking of amyloid precursor protein (APP) critically influences amyloidogenic processing, yet the mechanisms regulating this pathway remain incompletely defined. The exocyst is a highly conserved, insulin-responsive, eight-protein Rab effector complex that directs intracellular transport vesicle targeting and docking. We identified APP in a proteomics screen of neuronal cell surface proteins altered after chemical inhibition of exocyst activity. In SH-SY5Y cells expressing a mutant APP that enhances amyloidogenic processing, RNAi-mediated silencing of exocyst subunits significantly decreased sAPP and Aβ secretion, leading to significant intracellular APP accumulation. We found high-resolution co-localization of APP with exocyst subunits in soma and neurites of differentiated human SH-SY5Y neurons and mouse primary hippocampal neurons, and live-cell TIRF microscopy identified highly coordinated movement between fluorescently-tagged exocyst and APP proteins. These interactions were confirmed in these cells and in mouse brain histological sections by proximity ligation assays (PLAs) demonstrating close (<40nm) APP-EXOC5 association. To examine if exocyst activity in neurons is regulated by insulin, as it is in adipocytes and muscle, we generated a SH-SY5Y cell line with pHluorin-tagged GLUT4. Inhibition of the exocyst prevented exocytosis of GLUT4 to the plasma membrane in response to insulin. Additionally, using PLAs in mouse primary hippocampal neurons and SH-SY5Y neurons, we found that GLUT4-EXOC5 associations were increased by insulin signaling, but APP-EXOC5 associations were markedly reduced, indicating insulin-dependent retargeting of the exocyst complex away from APP+ vesicles towards GLUT+ vesicles. All together, these data identify the exocyst as a novel insulin-regulated mediator of neuronal APP trafficking and Aβ secretion.
    In Brief: We show that the insulin-responsive exocyst regulates amyloidogenic processing of APP in neurons and that insulin signaling shifts the exocyst away from APP trafficking to promote the translocation of GLUT4-containing vesicles to the plasma membrane of neurons.
    DOI:  https://doi.org/10.64898/2026.04.14.717551
  44. Transl Neurodegener. 2026 Apr 29. pii: 20. [Epub ahead of print]15(1):
    A new dawn for Parkinson's disease: commentary on the emergence of stem cell-based therapies.
    Rosalie Elvira, Wai Hon Chooi, Hongyan Wang, Eng King Tan, Zhi Dong Zhou.
      The field of regenerative medicine for Parkinson's disease (PD) has reached a pivotal moment. After decades of preclinical research, recent first-in-human clinical trials demonstrated that cell replacement therapy using stem cell-derived dopaminergic neurons is not only feasible and safe but also shows promising signs of efficacy. Here we analyze three landmark 2025 studies, including the phase I/II trial of allogeneic induced pluripotent stem cell-derived dopaminergic progenitors, that mark a significant leap forward for PD therapy. We discuss principles underpinning the therapy, the historical context of fetal tissue transplants, findings from recent trials, and critical challenges. The convergence of robust cell manufacturing, precise stereotactic surgery, and advanced neuroimaging provides compelling evidence that stem cell-based therapies are potentially a viable treatment paradigm for PD.
    Keywords:  Clinical trials; Dopaminergic neurons; Parkinson’s disease; Stem cell-based therapies
    DOI:  https://doi.org/10.1186/s40035-026-00556-2
  45. Small. 2026 Apr 30. e73577
    In Vitro Reconstruction of Axonal Heat Sensing with a Photothermal Nerve-on-a-Chip.
    Koji Sakai, Yujiro Tanaka, Riku Takahashi, Toichiro Goto, Yosuke Mizuno, Taiki Otomo, Aya Tanaka.
      Axons are the initial sites of thermal signal detection and transduction, but their localized response to heat remains poorly characterized. Here, we present a photothermal nerve-on-a-chip platform that reconstructs in vitro the key elements of axonal thermosensation. By integrating graphene-based photothermal heaters with microelectrode arrays inside axon-guiding microchannels, the platform enables localized, millisecond-scale thermal stimulation and simultaneous extracellular recording of action potentials. Using this platform, we uncovered rapid and reproducible heat-evoked responses in rat dorsal root ganglion neurons, including thermoreceptor-mediated rapid desensitization. With its ability to distinguish stimulus-locked and inter-pulse activity, we also observed distinct thermal-response profiles in human iPSC-derived sensory neurons, characterized by delayed heat responsiveness. Our platform enables high-resolution analysis of axonal temperature coding and is a scalable tool for exploring peripheral thermosensation in development and disease.
    Keywords:  axon physiology; graphene; microelectrode array; microfluidic device; neuroengineering; organ‐on‐a‐chip; thermosensation
    DOI:  https://doi.org/10.1002/smll.73577
  46. Cell Prolif. 2026 May 01. e70223
    Next-Generation Strategies for Neural Repair and Regeneration: Neural Organoid Transplantation in the CNS.
    Yutong Wang, Jinrui Li, Xingjia Mao, Wanyu Wang, Yansong Li, Xuefei Hu, Jinjie Zhong, Fengdong Zhao, Linlin Wang.
      Neurological disorders are often devastating and notoriously difficult to repair, creating an urgent need for novel research models and therapeutic strategies. Neural organoids-three-dimensional, self-assembling structures derived from stem cells-have emerged as a powerful platform to address this challenge. Supported by enabling technologies like bioreactors and 3D printing, advanced maturation protocols have significantly enhanced their cellular diversity and functional utility. This progress has paved the way for their widespread application in developmental studies, disease modelling, and notably, regenerative medicine. Focusing specifically on the latter, this article reviews how neural organoid transplantation opens new avenues for treating CNS injuries and degeneration. We first elaborate on the development, characteristics, and maturation strategies of neural organoids. We then summarise the translational applications and achievements of transplanting both whole neural organoids and their derived vesicles, analyse the prevailing challenges in the field, and finally, outline future directions to advance the therapeutic potential of this technology.
    Keywords:  characteristics; maturation; neural organoids; repair and regeneration; transplantation
    DOI:  https://doi.org/10.1111/cpr.70223
  47. bioRxiv. 2026 Apr 17. pii: 2026.04.16.719007. [Epub ahead of print]
    Lysosomal Profiling with LysoTracker for Quantitative Assessment of Cellular Senescence in Human Fibroblasts.
    Javier Estrada, Scott Tenenbaum, Melinda Larsen, Thomas J Begley, J A Melendez.
      Cellular senescence is a stable cell-cycle arrest state associated with characteristic phenotypes, including enlarged cell morphology, altered secretory signaling, and pronounced lysosomal remodeling. Senescent cells commonly accumulate increased numbers of enlarged lysosomes with changes in acidity and degradative capacity, creating an opportunity for simple live-cell readouts of senescence-linked organelle remodeling. Here, I describe a live-cell lysosomal profiling protocol that uses LysoTracker Deep Red, an acidotropic fluorescent dye, to label and quantify acidic organelles in individual living cells as an indicator of senescence-associated lysosomal expansion. The method is demonstrated in IMR-90 human lung fibroblasts undergoing replicative senescence across serial passaging. The protocol details cell culture and passage tracking, LysoTracker staining, fluorescence imaging, and straightforward image-based quantification of lysosomal signal intensity and lysosome-enriched area per cell. As an optional validation step, senescence-associated β-galactosidase staining is performed on parallel cultures to confirm senescent cell identity. Representative outcomes show increased LysoTracker signal and expanded lysosome-enriched regions in late-passage cultures compared to early-passage controls, consistent with lysosomal remodeling during senescence. This protocol is designed to be simple to adopt and can be adapted to other cell types or senescence-inducing stresses, providing a practical, quantitative complement to conventional endpoint assays.
    SUMMARY: This article presents a live-cell imaging protocol using LysoTracker Deep Red to quantify lysosomal remodeling as a marker of cellular senescence in IMR-90 human fibroblasts. We demonstrate quantitative lysosomal readouts derived from fluorescence imaging, including lysosome-enriched area and intensity measurements that can be summarized per cell and, when desired, as stitched-field, per-nucleus normalized metrics. Senescence status can be validated against senescence-associated β-galactosidase (SA-β-Gal) staining performed on parallel cultures. The method can be adapted to other cell types or senescence-inducing stresses and enables quantitative analysis of lysosomal remodeling during senescence.
    DOI:  https://doi.org/10.64898/2026.04.16.719007
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