bims-axbals 2026-08-16 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2026–08–16
forty papers selected by
TJ Krzystek

The structural basis for LRRK2's activation and autoinhibition.
Initial Molecular Detection of Membrane Damage in Post-Golgi Compartments.
Functional characterization of human iPSC-derived sensory neuron processes in microfluidic cultures.
RAN Translation-Coupled Decay of the C9orf72 GGGGCC Repeat Transcript by the RNA Exosome Suppresses Dipeptide Repeat Production.
The UNC13A cryptic exon associates with cognitive impairment in Alzheimer's disease.
Deletion of the calcium-binding protein S100β alters axon initial segment development in the visual cortex.
Advanced imaging of membrane contact sites.
Calcium-Dependent Cytoskeletal Collapse and Recovery of Axons After Partial Laser Ablation.
Sorcin couples Annexin A11 recruitment to ESCRT-III assembly for plasma membrane repair.
Persistent export bias of TDP-43 under native autoregulation links insoluble accumulation to nuclear dysfunction.
An expanding role for ATG8s and ATG8 E3-like ligases in maintaining membrane integrity.
Parkinson's disease-associated PINK1 loss disrupts ensheathing glia and causes dopaminergic neuron synapse loss.
Circular RNAs in amyotrophic lateral sclerosis.
The Interactions of Tau, RNA, and Stress Granules in Neurodegenerative Disease: A Comprehensive Review.
Modular Tissue-Engineered Motor Units Featuring Spinal Motor Neurons Innervating Self-Assembled Myofiber Bundles.
Structural Heterogeneity of TDP-43 Fragments in Alzheimer's Disease and Primary Age-Related Tauopathy by Artificial Intelligence (AI)-Based 3D Segmentation.
A Split-Luciferase Complementation Assay for Temporally Resolved Measurement of Tau Clearance in Microglia.
Regulation and roles of mammalian mitophagy.
Distinct cellular phenotypes of language and executive decline in amyotrophic lateral sclerosis.
Identifying candidate therapeutic targets in amyotrophic lateral sclerosis through a transcriptome-wide machine-learning consensus approach for drug repurposing.
Research progress on the α-synuclein-lysosome axis in Parkinson's disease: molecular mechanisms of protein aggregation, autophagy dysfunction, and therapeutic targeting.
Molecular insights of peroxisome proliferator-activated receptor-γ signalling in amyotrophic lateral sclerosis and Huntington's disease.
Selective loss of primary cilia and neurotrophic signaling in G51D α-synuclein mice highlights a common pathway to Parkinson's disease.
[Yeast as a Biochemical Model for Diseases Associated with Impaired Intracellular Proteolytic Systems].
Mechanism of Autophagic Extracellular Vesicles Revealed.
Evaluation of genetic instability in patients with amyotrophic lateral sclerosis.
The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.
Human iPSC-derived heart valve-like assembloids model valve development and disease pathology.
The role of N-glycans and their processing in ER-to-lysosome-associated degradation of disease-causing mutant Neuroserpin.
Epigenetic drift and LINE-1 activation in aging brain: Implications for neurodegenerative disease.
Selective Brain-Penetrant TTBK1 Inhibitors Modulate TDP-43 Pathology and Rescue Cognitive Deficits in a Mouse Model of TDP-43 Proteinopathy.
Exploring viscosity sensitivity of π-extended coumarin fluorogen-based PRPGs for precise photorelease of valproic acid: detection and defibrillation of TDP-43 aggregation.
Photostimulation improves maturation of human photoreceptors.
New insights into the molecular regulation of bridge-like lipid transfer proteins revealed by the Atg2-Atg18 structure.
Retinal ganglion cell autophagy: a housekeeper essential for neuronal homeostasis and survival.
Neurogenesis defects in iPSC-derived midbrain organoids of early-onset Parkinson's disease with 22q11.2 deletion syndrome.
PRKCD Orchestrates Sevoflurane-Induced Cognitive Dysfunction in Aged Rats by Regulating PINK1/PRKN Mitophagy Pathway.
A live-cell autophagy reporter reveals reversible vacuolation in naked mole-rat skin fibroblasts under lysosomal stress.
A quantitative model of a phenotypically variable genetic defect.
α-Synuclein burden amplification in Parkinson's disease: a unified genetic, molecular, and cellular framework.

Cell. 2026 Aug 10. pii: S0092-8674(26)00825-1. [Epub ahead of print]

The structural basis for LRRK2's activation and autoinhibition.

Amalia Villagran Suarez, Kathryn S Hatch, Tatyana Bodrug, Wei Gai, Katherine J Surridge, Elizabeth Moussikhina, Kendrick H V Nguyen, Marta Sanz-Murillo, Robert Callahan, Erica Xiong, Delisa Ramos, Lawrence Zhu, Verena Dederer, Sebastian Mathea, Janet Iwasa, Stefan Knapp, Kevan M Shokat, Samara L Reck-Peterson, Andres E Leschziner.

  Mutations in leucine-rich repeat kinase 2 (LRRK2) are the second most common cause of autosomal-dominant Parkinson's disease (PD), and increased LRRK2 kinase activity is also observed in idiopathic PD, making LRRK2 a major actionable therapeutic target. LRRK2 is a 286-kDa multidomain enzyme containing a Ras-like GTPase (ROC) and a kinase domain. Using cryo-electron microscopy (cryo-EM), biochemical reconstitution, and cell-based assays, we show that the ROC GTPase governs switching between autoinhibited and active states: GTP binding promotes activation, whereas GDP binding enforces autoinhibition. Two common PD-linked mutations, G2019S and R1441C/G/H, activate LRRK2 through distinct structural mechanisms, revealing genotype-specific routes to dysregulation. These findings provide a unified framework for understanding LRRK2 regulation with broad therapeutic implications. Stabilizing the guanosine diphosphate (GDP)-bound state may inhibit LRRK2 by maintaining autoinhibition, whereas promoting the GTP-bound state could be advantageous in specific cellular contexts, such as the lung, where increased LRRK2 kinase activity may play protective or regulatory roles.

Keywords:  G2019S; GTPase; LRRK2; Parkinson’s disease; R1441C; R1441H; activation; autoinhibition; cryo-EM; kinase

DOI:  https://doi.org/10.1016/j.cell.2026.07.027
Cells. 2026 Jul 30. pii: 1375. [Epub ahead of print]15(15):

Initial Molecular Detection of Membrane Damage in Post-Golgi Compartments.

Yoko Shiba, Nana Saito.

  Mammalian cells contain numerous membrane-bound organelles, of which endosomes serve as the initial destination for endocytosed molecules. Therapeutic agents are also internalized by cells and transported to endosomes or phagosomes and subsequently delivered to lysosomes for degradation. Therefore, these agents require drug delivery systems (DDSs) that enable their escape from endosomes into the cytosol before lysosomal degradation; however, endosomal escape is a major limitation of current DDSs. Studies of bacterial phagosomal escape have revealed mechanisms by which host cells detect damage to organelle membranes. These membrane damage-sensing molecules also recognize membrane damage caused by artificial DDSs or physical energy-based insults. In this review, we summarize the molecular mechanisms underlying the early stages of membrane damage in the plasma membrane, lysosomes and bacteria-containing vacuoles (BCVs) to better understand the early stages of endosomal membrane damage in the absence of pathogens. We summarize recent advances in galectins, endosomal sorting complexes required for transport (ESCRT) complexes, sphingomyelin, stress granules, and phosphatidylinositol 4-phosphate (PI4P) at membrane contact sites, as well as annexins. We also discuss the recruitment kinetics of these molecules to damaged membranes. Although the recruitment kinetics vary depending on cell type and experimental conditions, this information provides a timeframe for the events following membrane damage, including damage sensing, membrane repair, and degradation of damaged organelles. We also discuss a potential fourth event, fusion between the plasma membrane and endosomes or lysosomes for membrane repair in the annexin section. Finally, we summarize approaches for inducing "sterile" endosomal membrane damage. Future development of these approaches may facilitate the design of novel DDSs and physical energy-based strategies for manipulating specific organelles.

Keywords:  ESCRT; PI4P; annexins; galectin; membrane damage; membrane repair by fusion; sphingomyelin

DOI:  https://doi.org/10.3390/cells15151375
Stem Cells Transl Med. 2026 Jul 20. pii: szag065. [Epub ahead of print]15(8):

Functional characterization of human iPSC-derived sensory neuron processes in microfluidic cultures.

Laura Kleckner, Omar Mossad, Anil Kumar Kalia, Ramin Raouf.

  Rodent cell culture models have long underpinned research into nociceptive signaling; however, their limited recapitulation of human nociceptor biology has created a translational gap in analgesic development. While primary human sensory neurons are relevant, their use is hampered by scarcity, ethical constraints, donor variability, and difficulties in long-term culture. Furthermore, conventional cultures lack the compartmentalization needed to study sensory neuron processes and fail to recapitulate the synaptic connectivity between sensory and spinal cord neurons, limiting their translational relevance. To address these limitations, we utilized a microfluidic platform enabling compartmentalized culture of human induced pluripotent stem cell (hiPSC) derived sensory neurons (hiPSC-SNs) to study the function of their processes. We also demonstrate the feasibility of microfluidic co-cultures of hiPSC-SN with human iPSC-derived cortical excitatory neurons (hiPSC-CNs) as a basis for future development of models for sensory-to-CNs communication circuit. Using optimized protocols, we maintained stable microfluidic cultures and confirmed expression of pain-relevant sodium channels (Nav1.7, Nav1.8) in hiPSC-SN in both mono- and co-culture configurations. Leveraging this compartmentalized platform, we demonstrate that pharmacological blockade of Nav1.7 and Nav1.8 inhibits signal propagation along sensory neuron processes. We also demonstrate that growth factors modulate excitability of these processes. This functional validation underscores the platform's capability to investigate signal transmission along human sensory processes and demonstrates its potential for modelling more complex cellular interactions. Thus, we present a human iPSC-based microfluidic culture model that enables detailed study of sensory neuron processes and assessment of analgesics targeting nociceptive transmission, offering a significant advance toward analgesic drug discovery.

Keywords:  Nav1.7; Nav1.8; compartmentalization; iPSC-derived sensory neurons; microfluidic culture; signal propagation

DOI:  https://doi.org/10.1093/stcltm/szag065
Int J Mol Sci. 2026 Aug 04. pii: 6986. [Epub ahead of print]27(15):

RAN Translation-Coupled Decay of the C9orf72 GGGGCC Repeat Transcript by the RNA Exosome Suppresses Dipeptide Repeat Production.

You Wu, Li Li, Jing Tian, Leilei Liu, Kunzhao Du, Zhicheng Shao, Tianlin Cheng, Xin Cao, Tao Wang.

  The RNA exosome plays a critical role in surveilling nuclear mRNA biogenesis and regulating co-translational mRNA decay in the cytoplasm. Unlike canonical translation, repeat-associated non-AUG (RAN) translation of a GGGGCC hexanucleotide repeat expansion (HRE) within an intron of the C9orf72 locus leads to the synthesis of neurotoxic dipeptide-repeat (DPR) proteins, contributing to the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis (C9-ALS/FTD). However, it remains unclear whether aberrant RAN translation is monitored and regulated co-translationally or how C9orf72 HRE (C9-HRE) mRNA is degraded during this process. Here, we demonstrate that RAN translation triggers the rapid decay of C9-HRE mRNA. During this process, the RNA exosome engages the translating ribosome-C9-HRE mRNA complex to mediate RAN translation-coupled mRNA decay. Moreover, overexpression of EXOSC3, a key subunit of the RNA exosome cap, promotes RAN translation-coupled decay of C9-HRE mRNA and suppresses DPR production. In iPSC-derived neurons, a reduction in EXOSC3 levels blocks C9-HRE mRNA decay in a translation-dependent manner, further confirming its role in RAN translation surveillance. These findings highlight the essential function of the RNA exosome, particularly EXOSC3, in mitigating RAN translation-associated toxicity and preventing pathological DPR production. This work provides insights into potential therapeutic strategies for C9-ALS/FTD and may have broader implications for other disorders involving RAN translation.

Keywords:  C9orf72-ALS; RAN translation; RNA exosome; co-translational regulation; mRNA stability

DOI:  https://doi.org/10.3390/ijms27156986
Alzheimers Res Ther. 2026 Aug 14. pii: 187. [Epub ahead of print]18(1):

The UNC13A cryptic exon associates with cognitive impairment in Alzheimer's disease.

Madison M Reeves, Sara Aviles Carpintero, Matteo Zanovello, Karen Jansen-West, Mei Yue, Anna Calliari, Yuping Song, Judith Dunmore, Candela Maroto Cidfuentes, Sophie Ball, Jennifer M Kachergus, Heather E Killeen, Bailey Rawlinson, Erica Engelberg-Cook, Michael DeTure, Gregory S Day, Neill R Graff-Radford, Bradley F Boeve, David S Knopman, Ronald C Petersen, Melissa Murray, Aubrey E Thompson, Dennis W Dickson, Pietro Fratta, Leonard Petrucelli, Keith A Josephs, Mercedes Prudencio.

   BACKGROUND: TAR DNA-binding protein of 43 kDa (TDP-43) is often found in the brains of patients with Alzheimer's disease (AD), where it co-occurs with amyloid β plaques and tau neurofibrillary tangles, and associates with accelerated cognitive decline and brain atrophy. TDP-43's function of repressing the inclusion of cryptic exons (CEs) during RNA splicing is compromised in AD. A single-nucleotide polymorphism (SNP) located within the CE in the UNC13A gene [rs12973192 (C > G)] is associated with higher disease risk and reduced survival in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) by weakening TDP-43 binding promoting CE inclusion.
OBJECTIVE: To investigate the influence of the rs12973192 UNC13A CE SNP and UNC13A cryptic splicing on TDP-43 pathology, survival and cognitive impairment in AD.
METHODS: We evaluated the UNC13A CE SNP in a cohort of 1,672 AD, including 643 AD brains with available cognitive measurements and 73 AD cases for which we measured cryptic RNA levels in the amygdala. We also evaluated a cohort of 466,517 from the UK Biobank to determine associations between the UNC13A CE SNP and dementia diagnosis.
RESULTS: In AD, the UNC13A CE SNP associated significantly with cognitive decline, but not with TDP-43 pathology or with survival. UNC13A cryptic RNA levels in the amygdala were a better predictor of cognitive decline than the UNC13A CE SNP itself, while STMN2-another well-known CE target-exhibited no such association.
CONCLUSIONS: These findings point to UNC13A cryptic splicing as a specific driver of cognitive decline in AD, outperforming both genetic risk and other cryptic targets.

Keywords:  Alzheimer’s disease; Cognition; Cryptic exons; Dementia; STMN2; UNC13A

DOI:  https://doi.org/10.1186/s13195-026-02157-7
Front Cell Neurosci. 2026 ;20 1895033

Deletion of the calcium-binding protein S100β alters axon initial segment development in the visual cortex.

Yanis Inglebert, Rafael Sanz-Gálvez, Danna Quetzali Chavez Lorenzana, Eva Lafaverges, Arlette Kolta.

  The axon initial segment (AIS) is a key structure for fine-tuning neuronal excitability. It plays a particularly important role during development across many sensory systems, where it contributes to network refinement and the adjustment of excitability levels. In the visual cortex, the AIS undergoes a significant period of plasticity that helps adjust neuronal excitability during key developmental stages such as eye opening and the onset of binocular vision. This development is tightly regulated by numerous factors, including glial cells. The calcium-binding protein S100β, which is primarily expressed in astrocytes, has previously been implicated in axonal development. We therefore asked whether it might also contribute to the normal development of the AIS in the visual cortex. Here, we characterize the consequences of S100β loss on AIS development and examine its impact on neuronal excitability.

Keywords:  S100β; astrocytes; axon initial segment (AIS); development; visual cortex

DOI:  https://doi.org/10.3389/fncel.2026.1895033
Nat Cell Biol. 2026 Aug;28(8): 1612-1625

Advanced imaging of membrane contact sites.

Riccardo Filadi, Ambra Bertocco, Michela Rossini, Paola Pizzo.

Organelle membrane contact sites (MCSs) coordinate key cell activities and their alterations are associated with several high-incidence disorders, prompting an increasing interest in their study. However, the investigation of MCSs is challenging, mostly because of their nanometric size and dynamic nature. Here we highlight the methods that are available for analysing MCSs. We focus on advanced imaging techniques and discuss their advantages and limitations, providing practical guidance for researchers approaching this field. We propose to study MCSs through a combination of different methodologies, complementing their visualization with investigation of the associated functions. To this end, we also discuss the need to develop innovative biosensors.

DOI: https://doi.org/10.1038/s41556-026-02003-w
J Neurochem. 2026 Aug;170(8): e70539

Calcium-Dependent Cytoskeletal Collapse and Recovery of Axons After Partial Laser Ablation.

Ashish Mishra, Pooja Joshi, Md Arsalan Ashraf, Pramod Pullarkat.

  Traumatic stretch or crush injury to axons causes widespread and often irreversible damage to the axonal cytoskeleton, in which calcium-mediated breakdown is known to play a central role. Unlike complete transection, where recovery must proceed through formation of a new growth cone, milder injury can disrupt the axonal cytoskeleton while leaving the plasma membrane intact. How the cytoskeleton fails, and how it can recover, under these conditions remains unclear. Here we address this using a partial laser-ablation method that damages the cytoskeleton and evokes a calcium transient while preserving membrane continuity. We show that the ensuing cytoskeletal retraction is set by a mechanical balance between acto-myosin contractility and microtubule stability: stabilizing microtubules or inhibiting acto-myosin contractility suppresses retraction. Moreover, chelating extracellular calcium mitigates degeneration and, in a subset of axons, permits complete recovery. We also show that microtubules and actin filaments show distinct loss and recovery dynamics and provide a hypothesis for the "burning-fuse" -like depolymerization of the microtubule bundle. These findings provide insights into how the axonal cytoskeleton collapses and recovers after injury and suggest strategies for mitigating damage.

Keywords:  axonal cytoskeletal mechanics; axonal injury; axonal microtubules; calcium signaling in axons; laser ablation

DOI:  https://doi.org/10.1111/jnc.70539
Proc Natl Acad Sci U S A. 2026 08 18. 123(33): e2610420123

Sorcin couples Annexin A11 recruitment to ESCRT-III assembly for 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 PM integrity to prevent cell death. Genetic loss of PM repair factors is associated with human diseases such as muscular dystrophy. 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 remains unclear. Here, leveraging quantitative organellar proteomics and genome-wide CRISPR interference screens, we identify sorcin as a PM repair factor that couples annexin A11 (ANXA11)-mediated sensing of PM damage to ESCRT-III assembly. We show that sorcin directly binds ANXA11 and ALIX in the presence of Ca2+ via its penta-EF-hand domain and flexible N terminus, respectively, and is required for ESCRT-III recruitment to PM lesions and membrane resealing. Our data support a model in which ANXA11, recruited to the PM upon damage-induced Ca2+ influx, serves as an anchor that facilitates the sequential recruitment of sorcin and ESCRT-III at PM lesions. Together, these findings establish a Ca2+-dependent scaffolding mechanism that couples PM damage sensing to ESCRT-III assembly for PM repair.

Keywords:  annexin; endosomal sorting complex required for transport (ESCRT); membrane repair; plasma membrane

DOI:  https://doi.org/10.1073/pnas.2610420123
Neurobiol Dis. 2026 Aug 04. pii: S0969-9961(26)00305-0. [Epub ahead of print]228 107560

Persistent export bias of TDP-43 under native autoregulation links insoluble accumulation to nuclear dysfunction.

Genri Toyama, Shingo Koide, Takuma Yamagishi, Aya Washida, Ryutaro Hanyu, Osamu Onodera, Akihiro Sugai.

  Nuclear depletion and cytoplasmic mislocalization of TDP-43 are central pathological features of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 protein levels are normally maintained by autoregulation through its native 3' untranslated region (3' UTR), but whether this feedback remains protective during chronic cytoplasmic bias is unclear. To address this, we engineered full-length human TDP-43 carrying an N-terminal nuclear export signal (NES) while retaining the native 3' UTR autoregulatory module. In HEK293T cells, NES insertion imposed cytoplasmic bias and promoted detergent-insoluble TDP-43 species. In differentiated SH-SY5Y cells, nuclear splicing defects and autoregulatory changes scaled with export-biased load; detergent-insoluble accumulation was already detectable within a low-load range, defined by whole-cell RIPA-soluble exogenous TDP-43 ≤ 30% of endogenous levels. Human iPSC-derived neurons showed a comparable cytoplasmic shift, discrete TDP-43-immunoreactive foci, and TDP-43-dependent splicing defects. Endogenous TARDBP depletion provided a functional rescue test: nuclear-competent WT-TDP-43-3' UTR restored TDP-43-dependent nuclear readouts, whereas NES-TDP-43-3' UTR did not. In the NES condition, weakened autorepression increased transgene-derived TARDBP transcripts, but the added output failed to expand the soluble, splice-competent pool and instead partitioned into insoluble fractions. Increasing soluble NES-TDP-43 to endogenous-equivalent levels likewise did not normalize splicing, indicating that abundance alone is insufficient when output remains export-biased. These findings support a model in which persistent export bias converts native TARDBP autoregulation into maladaptive feedback: compensatory output is uncoupled from productive nuclear recovery and diverted toward cytoplasmic insoluble/fragmented species.

Keywords:  3′ UTR-mediated autoregulation; ALS/FTLD; Detergent-insoluble TDP-43; Nuclear export signal (NES); TDP-43-dependent splicing

DOI:  https://doi.org/10.1016/j.nbd.2026.107560
Autophagy. 2026 Aug 13. 1-11

An expanding role for ATG8s and ATG8 E3-like ligases in maintaining membrane integrity.

Dale P Corkery, Yao-Wen Wu.

  Endolysosomal membranes are frequently damaged by pathogenic stress associated with aging, infection, and neurodegeneration, and failure to repair such damage leads to inflammation and cell death. Recent advances identify membrane ATG8 conjugation (atg8ylation) as a key process that links damage detection to coordinated lysosomal repair, removal, and regeneration. Beyond its canonical role in macroautophagy, membrane atg8ylation also occurs on preexisting, non-autophagosomal single membranes through Conjugation of ATG8s to Single Membranes (CASM), positioning this pathway as a rapid response to membrane stress. Two E3-like ligase complexes, ATG16L1-ATG5-ATG12 and TECPR1-ATG5-ATG12, act as complementary sensors of lysosomal injury by detecting distinct physicochemical cues, including proton gradient collapse and lipid scrambling. These ligases convert damage signals into spatially restricted membrane atg8ylation, generating a membrane-associated platform that coordinates multiple downstream pathways. These include ESCRT-dependent membrane repair, ER-lysosome lipid transfer, membrane tubulation, and stress granule formation. When repair fails, membrane atg8ylation regulates lysophagy and activates lysosomal biogenesis and regeneration to restore lysosomal homeostasis. These emerging findings define membrane atg8ylation as a central organizer of membrane quality control rather than a pathway merely confined to macroautophagy. In this review, we summarize the current understanding of how membrane atg8ylation detects lysosomal damage and how this pathway coordinates other lysosomal quality control mechanisms to maintain lysosomal integrity.

Keywords:  CASM; Lysosome; lysosomal membrane integrity; membrane atg8ylation; noncanonical autophagy

DOI:  https://doi.org/10.1080/15548627.2026.2704442
Elife. 2026 Aug 13. pii: RP105386. [Epub ahead of print]14

Parkinson's disease-associated PINK1 loss disrupts ensheathing glia and causes dopaminergic neuron synapse loss.

Lorenzo Ghezzi, Sabine Kuenen, Ulrike Pech, Nils Schoovaerts, Ayse Kilic, Suresh Poovathingal, Kristofer Davie, Jochen Lamote, Roman Praschberger, Patrik Verstreken.

  Parkinson's disease (PD) is commonly associated with the loss of dopaminergic neurons in the substantia nigra, but many other cell types are affected even before neuron loss occurs. Recent studies have linked oligodendrocytes to early stages of PD, though their precise role is still unclear. PINK1 is mutated in familial PD, and through unbiased single-cell sequencing of the entire brain of Drosophila Pink1 models, we observed significant gene deregulation in ensheathing glia (EG), cells that share functional similarities with oligodendrocytes. We found that the loss of Pink1 leads to abnormalities in EG, similar to the reactive response of EG seen upon nerve injury. Using cell-type-specific transcriptomics, we identified deregulated genes in EG as potential functional modifiers. Specifically downregulating two trafficking factors in EG, Vps35 and Vps13, also mutated in PD, was sufficient to rescue neuronal function and protect against dopaminergic synapse loss. Our findings demonstrate that Pink1 loss in neurons triggers an injury-like response in EG, and that Pink1 loss in EG, in turn, disrupts neuronal function. Vesicle trafficking components, which may regulate membrane interactions between organelles in EG, seem to play a role in maintaining neuronal health and ultimately preventing dopaminergic synapse loss. Our work highlights the essential role of glial support cells in the pathogenesis of PD and identifies vesicle trafficking within these cells in disease progression.

Keywords:  D. melanogaster; Parkinson's disease; Pink1; glial cell; neuron-glia interactions; neuroscience

DOI:  https://doi.org/10.7554/eLife.105386
Neurobiol Dis. 2026 Aug 14. pii: S0969-9961(26)00319-0. [Epub ahead of print] 107574

Circular RNAs in amyotrophic lateral sclerosis.

Reza Ataei, Javad Amini, Nima Sanadgol, Anne F Simon, Martin L Duennwald.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, with most cases lacking a clear genetic basis. Emerging evidence highlights the involvement of non-coding RNAs, particularly circular RNAs (circRNAs), in disease onset and progression. Here, we investigated circRNAs implicated in ALS and related motor neuron diseases (MNDs). Here we provide a general overview of circular RNA metabolism and cellular functions. We then present our systematic literature review that identified ALS-associated circRNAs, followed by in silico analyses of 15 circular RNA candidates that were selected based on most compelling data regarding ALS. Our results revealed that several circular RNAs regulate ALS-related genes, such as unfolded protein response, oxidative stress, cell cycle regulation, and apoptosis. Protein-RNA interaction analysis further showed that ALS-related circRNAs can sponge 20 RNA-binding proteins. Additionally, molecular docking analysis demonstrated that ALS-associated FUS variants significantly alter its binding affinity to circular RNAs. RNA-seq data from ALS patients confirmed significant alterations in the expression of host genes of ALS-related circRNAs and hub proteins in ALS-affected CNS tissues. Collectively, our findings identify circRNAs as potential key contributors to ALS pathogenesis.

Keywords:  Amyotrophic lateral sclerosis (ALS); Circular RNAs (circRNAs); FUS; miRNA sponging

DOI:  https://doi.org/10.1016/j.nbd.2026.107574
Cells. 2026 Jul 29. pii: 1365. [Epub ahead of print]15(15):

The Interactions of Tau, RNA, and Stress Granules in Neurodegenerative Disease: A Comprehensive Review.

Tristyn N Garza, Jose F Abisambra.

  The discovery of RNA in the late 19th century revolutionized the understanding of cell biology. Subsequent discoveries over the next six decades revealed a key role for RNA in protein synthesis. Nevertheless, today, the mechanisms driving RNA metabolism remain enigmatic. Given its fundamental cellular role, RNA alterations are strongly linked to disease, including devastating neurodegenerative disorders pathologically defined by the accumulation of RNA-binding proteins. For example, the mislocalization of TDP-43, an RNA-binding protein, is a pathological feature of amyotrophic lateral sclerosis and frontotemporal dementia TDP-43. Another group of more than 20 neurodegenerative disorders, called tauopathies, is characterized by the aberrant accumulation of the protein tau. Similarly, the emerging concept that tau binds RNA, facilitating the formation of pathological structures, highlights the importance of RNA stability in tauopathies. However, the dynamics and consequences of RNA-tau interactions remain unclear. This review comprehensively catalogs key findings linking tau, RNA, and stress granules. These findings are important because they could offer novel opportunities to design therapeutic strategies.

Keywords:  RNA; neurodegeneration; neurodegenerative disease; stress granules; tau

DOI:  https://doi.org/10.3390/cells15151365
Macromol Biosci. 2026 Aug;26(8): e00660

Modular Tissue-Engineered Motor Units Featuring Spinal Motor Neurons Innervating Self-Assembled Myofiber Bundles.

Melanie C Hilman, Elizabeth N Krizman, Foteini Mourkioti, Suradip Das, D Kacy Cullen.

  A motor unit is the functional unit of muscle contraction, consisting of a population of skeletal muscle fibers innervated by axon terminals from a motor neuron. Tissue engineering strategies are being pursued to treat neuromuscular injuries by mimicking aspects of native myofascicular architecture; however, the critical role of innervation in myofiber development is often overlooked. Our group previously developed a pre-innervated tissue-engineered muscle on nanofiber sheets, demonstrating that innervation facilitated myofiber maturation and function in vitro. The current study builds on this framework to biofabricate pre-innervated three-dimensional (3D) bundles of individual myofibers that more closely replicate in vivo architecture. Specifically, we established a methodology to generate centimeter-scale Tissue Engineered Motor Units (TEMUs) comprising aligned myofiber bundles within a collagenous hydrogel and innervated by axons projecting from discrete population(s) of spinal motor neurons. A custom-built polydimethylsiloxane micro-scale channel system facilitated the alignment and self-assembly of myoblasts. The presence of aggregated motor neurons and axonal integration significantly enhanced myofiber maturation and contractility compared to non-innervated controls. We also evaluated the effects of media constituents on myofiber maturation, as assessed by myocyte fusion and sarcomere formation. Importantly, this TEMU biofabrication protocol is fully scalable, generating modular myofiber bundles at least 8 cm in length that can be aligned in parallel to achieve large-scale myofiber macro-bundles. TEMUs address key challenges in muscle tissue engineering by providing a 3D biofidelic platform to study the role of innervation in muscle development and function in vitro, as well as an implantable composite tissue to facilitate muscle replacement after severe trauma.

Keywords:  biomaterial scaffold; innervation; myofiber; neuromuscular junction; skeletal muscle; tissue engineering

DOI:  https://doi.org/10.1002/mabi.202500660
Neuropathol Appl Neurobiol. 2026 Aug;52(4): e70096

Structural Heterogeneity of TDP-43 Fragments in Alzheimer's Disease and Primary Age-Related Tauopathy by Artificial Intelligence (AI)-Based 3D Segmentation.

Gokhan Uruk, Rodolfo G Gatto, Nadia Hossain, Jennifer L Whitwell, R Ross Reichard, Keith A Josephs.

  TAR DNA-binding protein 43 (TDP-43) inclusions are defining pathological features of frontotemporal lobar degeneration (FTLD) but are also often observed in Alzheimer's disease (AD) and primary age-related tauopathy (PART). TDP-43 in AD is either associated with cognitive impairment or a protective-life prolonging impact, and yet the localization, cellular and fragment characteristics of TDP-43 need to be determined. We investigated the relationships between TDP-43 volumetric inclusion burden in low likelihood AD (lAD) and definite PART by immunostaining against phosphorylated TDP-43 (pTDP-43), TDP-43 C terminal (TDP-C) and TDP-43 N-terminal (TDP-N) fragments combined with 3D confocal imaging taken from eight regions: amygdala (basolateral [amygdala-BL] and centromedial amygdala [amygdala-CM]), the hippocampus (Cornu Ammonis [CA]-1, CA2/3, CA4, dentate gyrus [DG] and subiculum [SUB]) and entorhinal cortex (ERC) and artificial intelligence (AI)-based segmentation via object recognition, reconstruction and quantification. We found amygdala-CM in lAD and PART to have the overall greatest burden of pTDP-43 whereas TDP-N burden in amygdala-BL of PART cases was greater than other TDP-43 fragments. There was no difference in TDP-43 burden in hippocampal subfields in PART. However, CA2/3 region showed greater pTDP-43 burden while TDP-N stood out in DG and SUB. Multiple comparisons among the groups revealed that TDP-C was the only fragment showing differences among PART and lAD in CA2/3, DG and SUB regions. Overall, unbiased AI-based volumetric burden analysis pipeline demonstrated unique fragment aggregation patterns in the neurodegenerative processes of PART and AD.

Keywords:  Alzheimer's disease (AD); TAR DNA‐binding protein 43 (TDP‐43); TDP‐43 C terminal (TDP‐C); TDP‐43 N terminal (TDP‐N); artificial intelligence (AI); pTDP‐43; primary age‐related tauopathy (PART)

DOI:  https://doi.org/10.1111/nan.70096
J Vis Exp. 2026 Jul 24.

A Split-Luciferase Complementation Assay for Temporally Resolved Measurement of Tau Clearance in Microglia.

Daya Mena, Anna Vincze, Andrew Shultz, Jennifer N Rauch.

As the resident immune cells of the central nervous system, microglia are central regulators of brain homeostasis and key mediators of neurodegenerative disease. These cells continuously survey the neural environment and play a critical role in the recognition, internalization, and degradation of extracellular substrates, including misfolded and aggregated proteins such as pathological tau. Despite growing evidence implicating microglia in tau clearance, existing approaches to measure tau uptake and degradation lack the temporal resolution and sensitivity needed to fully capture these dynamic processes. Here, we developed a luminescence-based assay to quantitatively monitor tau clearance in human induced pluripotent stem cell (iPSC)-derived microglia. This platform leverages a split-luciferase-based complementation system to enable highly sensitive, real-time detection of tau in live cells, allowing for precise tracking of its intracellular processing. This assay is scalable and adaptable across multiple cell types, providing a versatile tool to interrogate endolysosomal pathways and cellular mechanisms governing tau handling in neurodegenerative diseases, including Alzheimer's disease.

DOI: https://doi.org/10.3791/71870
Nat Rev Mol Cell Biol. 2026 Aug 14.

Regulation and roles of mammalian mitophagy.

Sascha Martens, Ian G Ganley.

Mitochondria are essential metabolic and signalling hubs exposed to stress, and mitochondrial damage is highly detrimental to the cell. Mitophagy - the autophagy of mitochondria - is a key mechanism that maintains both mitochondrial integrity and metabolic flexibility. Mitophagy occurs via multiple pathways that either involve activation of PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin-protein ligase Parkin, or are independent of PINK1 and Parkin. Recessive mutations in PINK1 and PKRN (the gene that encodes Parkin) cause early-onset Parkinson's disease and have provided key mechanistic insights into mitophagy. However, emerging findings indicate that mitophagy is also executed by other molecular routes. Despite these molecular advances in mitophagy characterization, the physiological roles of these pathways in mammals and the specific contexts or conditions in which they operate remain poorly defined. This Review summarizes current understanding of PINK1-Parkin-dependent and independent mitophagy pathways, highlighting mechanistic distinctions and coordinated regulation. We also examine physiological and pathological triggers of mitophagy, as well as the expanding therapeutic potential of targeting mitophagy in disease.

DOI: https://doi.org/10.1038/s41580-026-01012-9
Cell. 2026 Aug 04. pii: S0092-8674(26)00806-8. [Epub ahead of print]

Distinct cellular phenotypes of language and executive decline in amyotrophic lateral sclerosis.

Joana Petrescu, Cláudio Gouveia Roque, Christopher A Jackson, Aidan C Daly, Zoé Butti, Kristy Kang, Obadele Casel, Matthew Leung, Luke Reilly, Jacqueline Eschbach, Brhan Gebremedhin, Karina McDade, Jenna M Gregory, Richard Bonneau, Colin Smith, Hemali Phatnani.

  Cognitive manifestations, including impairments in language and executive functions, are seen in amyotrophic lateral sclerosis (ALS), but the underlying mechanisms remain unclear. We mapped prefrontal cortex regions from ALS patients by integrating spatial and single-nucleus transcriptomics in a cognitively stratified patient cohort. We uncover that cognitive impairment in ALS is associated with distinct patterns of neuronal dysfunction and glial-vascular dysregulation that vary by region and cognitive subtype. Executive dysfunction is linked to reduced mitochondrial and synaptic activity in deep-layer dorsolateral prefrontal cortex neurons, whereas language-related deficits track with a diffuse pan-regional response involving glial and vascular abnormalities. Our analyses, validated by multiplexed imaging, further identify signatures in the prefrontal cortex that span both motor and cognitive phenotypes, including a multicellular gliosis response. The findings reveal that clinical heterogeneity in ALS is driven by phenotype-specific cellular interactions in motor and non-motor regions of the brain.

Keywords:  ALS; ALS-FTD; ALS-FTSD; cognitive heterogeneity; cognitive impairment in ALS; executive function; language; multimodal analysis; spatial biology; verbal fluency

DOI:  https://doi.org/10.1016/j.cell.2026.07.008
Neuroscience. 2026 Aug 14. pii: S0306-4522(26)00546-4. [Epub ahead of print]

Identifying candidate therapeutic targets in amyotrophic lateral sclerosis through a transcriptome-wide machine-learning consensus approach for drug repurposing.

Enrique J de Andrés-Galiana, Juan Luis Fernández-Martínez, Germán Morís.

  Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease for which effective disease-modifying therapies remain limited. This study aimed to derive internally recurrent ALS-associated transcriptional signatures and generate directionally interpretable drug-repositioning hypotheses using a consensus machine-learning framework. Two publicly available transcriptomic datasets from motor cortex (E-MTAB-2325) and blood (E-TABM-940) were analyzed using four feature-selection methods within 100 repetitions of 4-fold cross-validation. Probes recurrently selected in models achieving an accuracy of at least 0.90 were prioritized and examined using COGENA pathway enrichment and Connectivity Map drug-signature analysis. Fifteen qualifying models were obtained for the motor-cortex dataset and 55 for the blood dataset. No exact prioritized gene or probe identifier was shared between the two top-100 signatures, but pathway-level integration identified complementary evidence involving glial and immune regulation, proteostasis and vesicle trafficking, MAPK-related stress signaling, cytoskeletal and extracellular remodeling, and RNA-related processes. The motor-cortex dataset additionally emphasized astroglial support, glutamate handling, and inclusion-body regulation, whereas the blood dataset highlighted cytokine regulation and directionally heterogeneous immune, mitochondrial, and metabolic signals. Deferoxamine and disulfiram showed the clearest reversal-compatible profiles in motor cortex, whereas yohimbic acid and atovaquone showed reversal-compatible profiles in blood. Ciprofloxacin, prochlorperazine, and a compound group led by androsterone instead showed concordant connectivity. The results provide transparent, hypothesis-generating gene, pathway, and compound priorities, but they do not establish biomarkers, therapeutic efficacy, or clinical suitability and require validation in independent cohorts and experimental ALS models.

Keywords:  Amyotrophic lateral sclerosis; Drug repurposing; Machine learning; Pathway analysis; Transcriptomic connectivity; Transcriptomics

DOI:  https://doi.org/10.1016/j.neuroscience.2026.08.017
Front Neurosci. 2026 ;20 1885103

Research progress on the α-synuclein-lysosome axis in Parkinson's disease: molecular mechanisms of protein aggregation, autophagy dysfunction, and therapeutic targeting.

Jiaojiao Fu, Chuanxi Zhu, Zhenzhen Fan.

  Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized pathologically by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies, which predominantly consist of misfolded α-synuclein (α-Syn) aggregates. Recent advances have highlighted the critical role of the interplay between α-Syn and lysosomal function, termed the α-Syn-lysosome axis, as a central mechanism underlying PD pathogenesis. This review systematically summarizes the molecular mechanisms driving α-Syn aggregation and the lysosomal dysfunction contributing to impaired autophagy-lysosome pathway (ALP) activity. We further discuss emerging therapeutic strategies targeting this axis to restore lysosomal function and mitigate α-Syn toxicity. By integrating the latest findings from molecular biology, cell biology, and preclinical studies, this article aims to elucidate the complex regulatory network of the α-Syn-lysosome axis and provide a theoretical foundation for the development of novel therapeutic interventions for PD.

Keywords:  Parkinson’ s disease; autophagy; lysosome; protein aggregation; α-synuclein

DOI:  https://doi.org/10.3389/fnins.2026.1885103
Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00043-7. [Epub ahead of print]188 113-143

Molecular insights of peroxisome proliferator-activated receptor-γ signalling in amyotrophic lateral sclerosis and Huntington's disease.

Gopika Venu, Vignesh Pandi A, Antony Justin.

  Progressive neuronal loss is a hallmark of neurodegenerative diseases like Huntingtons disease (HD) and Amyotrophic lateral sclerosis (ALS) which are caused by convergent mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy and dysregulated cell death pathways. Both conditions share significant disruptions in metabolic and inflammatory signalling despite having different genetic origins and clinical manifestations; underscoring the necessity of pathway-oriented treatment approaches. In the central nervous system, peroxisome proliferator-activated receptor-γ (PPAR-γ), a ligand-activated nuclear receptor has become an important regulator of inflammation, redox homeostasis, mitochondrial biogenesis and cellular stress responses. After giving a thorough overview of PPAR-γ structure activation and transcriptional regulation and the PGC-1α-mediated mitochondrial biogenesis axis, this chapter delves deeply into its interactions with major signalling pathways such as NF-κB, Wnt/β-catenin Nrf2/ARE and the autophagy-apoptosis networks. With a focus on experimental data showing PPAR-γ signaling's neuroprotective, anti-inflammatory, antioxidant and metabolic regulatory roles the pathophysiology of ALS and HD is critically investigated. Lastly the need for improved biomarkers, tailored multi-target strategies and selective modulators is highlighted in the discussion of current therapeutic limitations and translational difficulties.

Keywords:  Autophagy; Mitochondrial dysfunction; Motor neurons; NF-κB; PGC-1α; PPAR-γ

DOI:  https://doi.org/10.1016/bs.irn.2026.05.014
Proc Natl Acad Sci U S A. 2026 08 18. 123(33): e2619797123

Selective loss of primary cilia and neurotrophic signaling in G51D α-synuclein mice highlights a common pathway to Parkinson's disease.

Yu-En Lin, Ebsy Jaimon, YoungDoo Kim, Annabeth Loftman, Aaran Vijayakumaran, Benjamin D W Belfort, Claire Y Chiang, Benjamin R Arenkiel, Huda Y Zoghbi, Suzanne R Pfeffer.

  Parkinson's disease is characterized by dopaminergic neuron loss and accumulation of α-synuclein aggregates in the brain. G51D α-synuclein knock-in mice provide a genetically and clinically relevant model of disease, exhibiting early olfactory deficits, age-dependent motor impairment, and progressive phospho-α-synuclein accumulation. In multiple Parkinson's disease models, striatal cholinergic and parvalbumin interneurons, as well as astrocytes, lose primary cilia and the neurotrophic signaling needed to sustain dopaminergic neurons. We show here that G51D α-synuclein mice share these phenotypes. Phospho-Ser129 α-synuclein accumulation correlates with cilia loss in cholinergic interneurons but not in spiny projection neurons that accumulate higher phospho-α-synuclein levels. In the piriform cortex, parvalbumin neurons lose primary cilia and downregulate Neurturin, potentially contributing to olfactory dysfunction. Within the peripheral olfactory epithelium, horizontal basal cells lose cilia, whereas multiciliated olfactory sensory neuron cilia remain intact. These findings reveal convergent cellular vulnerabilities across Parkinson's disease models and highlight a pathogenic role for impaired ciliary signaling.

Keywords:  Parkinson’s disease; alpha-Synuclein; neurotrophic signaling; primary cilia

DOI:  https://doi.org/10.1073/pnas.2619797123
Mol Biol (Mosk). 2026 May-Jun;60(3):60(3): 430-439

[Yeast as a Biochemical Model for Diseases Associated with Impaired Intracellular Proteolytic Systems].

A O Sosnovtseva, E S Starodubova, D S Karpov, V L Karpov.

  The degradation of intracellular proteins is a fundamental biological process necessary for maintaining cellular homeostasis, controlling the cell cycle, regulating signal transduction, and preventing the accumulation of toxic protein aggregates. Disorders of the proteolytic systems are implicated in the pathogenesis of numerous human diseases, including neurodegenerative diseases, lysosomal storage disorders, metabolic disorders, and certain types of cancer. The development of rudimentary and cost-effective models of these diseases for the purpose of evaluating novel pharmaceutical agents and elucidating the molecular mechanisms underlying disease pathogenesis constitutes a pivotal medical and biological undertaking. The proteolytic apparatus of the yeast species Saccharomyces cerevisiae has become a biochemical model organism of significant importance. This is due to its well-studied nature, low cost, ease of genetic manipulation, and evolutionary conservatism. The mechanisms of proteolytic system dysfunction can be studied in this organism. Furthermore, therapeutic approaches aimed at correcting these dysfunctional mechanisms can be sought.

Keywords:  autophagy; biochemical model; proteinopathy; ubiquitin-proteasome system; yeast

DOI:  https://doi.org/10.7868/S3034555326030045
Traffic. 2026 Sep;27(3): e70045

Mechanism of Autophagic Extracellular Vesicles Revealed.

Constantinos Demetriades, Thierry Galli.

Recent work by Mao and colleagues identifies a distinct class of small extracellular vesicles, termed autophagic extracellular vesicles (AEVs), generated from amphisomes upon autophagy induction. In this commentary, we discuss how this study provides important mechanistic insight into the coupling between autophagy and secretion. AEVs are molecularly and functionally distinct from canonical exosomes, being enriched in autophagy-related components such as LC3 and p62, and dependent on core ATG machinery for their biogenesis. Notably, their secretion is enhanced by autophagy induction and contributes to intercellular communication, particularly in the context of viral infection. These findings position amphisomes as critical sorting hubs that direct cargo toward either degradation or secretion, thereby integrating autophagic and endolysosomal pathways. We further highlight how these results intersect with prior evidence implicating SNARE-dependent mechanisms, including VAMP7 and stress-responsive regulators such as GRASP55, in unconventional secretion. Finally, we discuss key unresolved questions, particularly the mechanisms underlying the generation of small intraluminal vesicles within amphisomes and the role of ESCRT machinery in this process. Overall, the identification of AEVs adds a new layer of complexity to extracellular vesicle biology and opens new avenues for understanding how autophagy contributes to intercellular signaling in health and disease.

DOI: https://doi.org/10.1111/tra.70045
Mutat Res Genet Toxicol Environ Mutagen. 2026 Jul;pii: S1383-5718(26)00037-9. [Epub ahead of print]913 503953

Evaluation of genetic instability in patients with amyotrophic lateral sclerosis.

Hendrew J B C Souza, Kátina M Souza, Matheus B Dos Santos, Mariane A P Silva, Tony F Grassi, Maria V Destro, Mariana G Braz.

  Genetic instability has been reported in several neurodegenerative diseases, such as Alzheimer's and Parkinson's, but only a few studies have addressed sclerosis. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Micronuclei (MNi) and nuclear buds (NBUDs) are established markers of chromosomal instability, yet no data are available regarding a possible link between genetic instability and ALS. The novelty of this case-control study lies in the assessment of genetic instability in oral exfoliated cells from ALS patients (n = 20) and matched controls (n = 20), contributing to the identification of potential novel markers related to the molecular pathogenesis of this severe disorder. Groups were matched for age, sex, and lifestyle (p > 0.05). No significant differences were observed in MNi or NBUD frequencies between groups (p > 0.05). These findings suggest no association between ALS and MN/NBUD frequencies in oral cells.

Keywords:  Buccal mucosa; Human; Lou Gehrig disease; Micronucleus; Neurodegenerative disease

DOI:  https://doi.org/10.1016/j.mrgentox.2026.503953
Cells. 2026 Jul 29. pii: 1371. [Epub ahead of print]15(15):

The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.

Elena D Avdonina, Sergey I Kutsev, Aleksandr V Shestopalov.

  Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in the mitochondrial genome or nuclear genes encoding proteins essential for mitochondrial function. These conditions are characterised by progressive dysfunction of tissues with high energy demands, particularly the nervous and muscular systems. In recent years, increasing consideration has been paid to the role of autophagy-the cellular mechanism for the degradation and recycling of intracellular components in the pathogenesis of mitochondrial diseases. This review synthesizes current knowledge on molecular mechanisms of macroautophagy and selective forms of au-tophagy targeting specific organelles and structures: mitophagy, pexophagy, ribophagy, ER-phagy, aggrephagy, lipophagy, lisophagy, and nucleophagy. Using classic mitochondrial syndromes-Kearns-Sayre syndrome (KSS), MERRF, and MELAS, as well as various mitochondrial myopathies-as examples, we discuss experimental evidence indicating both compensatory activation of autophagy and its insufficiency or blockade at different stages. Furthermore, we examine the link between deficiencies of key fatty acid β-oxidation enzymes (VLCAD, MCAD, CPT2) and impaired autophagic flux, including secondary defects of mitophagy mediated by energy deficiency. The review systematises current understanding of how dysregulation of selective autophagy promotes the accumulation of damaged mitochondria, oxidative stress, inflammation, and cell death in mitochondrial diseases. Prospects for therapeutic modulation of autophagy as a potential approach to treating these disorders are discussed.

Keywords:  autophagy; fatty acid oxidation disorders; mitochondrial diseases; mitophagy; selective autophagy

DOI:  https://doi.org/10.3390/cells15151371
Cell Stem Cell. 2026 Aug 11. pii: S1934-5909(26)00271-7. [Epub ahead of print]

Human iPSC-derived heart valve-like assembloids model valve development and disease pathology.

Yuanhang He, Abbas Jalili, Carter B Jones, Haoting He, Lameck Beni, Daniel Lamont, Junqi Hu, Macy Yost, Lance A Davidson, Si-Yang Zheng, Guang Li.

  Heart valves maintain unidirectional blood flow, yet most understanding of their development and disease comes from animal models that do not fully capture human valve behavior. We present a human induced pluripotent stem cell (iPSC)-derived valve-like assembloid platform that models key aspects of in vivo valve features at the cellular and molecular levels. We found that mechanical forces, endothelial culture conditions, and fluidic shear stress respectively promote valve induction, maintenance, and extracellular matrix stratification. We further used this system to model human valve defects, including genetic mutations, injury, and hyperglycemia-related abnormalities. This assembloid platform enables the in vitro study of human valve development and disease mechanisms.

Keywords:  congenital valve deficiency; endothelial cell; endothelial-to-mesenchymal transition; hyperglycemia; mechanical force; organoid; valve; valve injury

DOI:  https://doi.org/10.1016/j.stem.2026.07.011
Autophagy Rep. 2026 ;5(1): 2712797

The role of N-glycans and their processing in ER-to-lysosome-associated degradation of disease-causing mutant Neuroserpin.

Carolin Hoefner, Ilaria Fregno, Maurizio Molinari.

  Most proteins synthesized in the endoplasmic reticulum (ER) are covalently modified upon addition of pre-assembled oligosaccharides to side chains of asparagine (N) residues. Processing of N-linked oligosaccharides by ER-resident glucosidases, mannosidases and glucosyltransferases determines the fate of the associated polypeptides. Terminally glucose residues are removed from N-glycans to interrupt the engagement of ER-resident glucose-binding chaperones and promote secretion of native polypeptides. Mannose residues are removed to target terminally misfolded proteins for dislocation across the ER membrane and clearance by the cytoplasmic ubiquitin proteasome system (ER-associated degradation, ERAD). Recent evidence highlights the role of persistent N-glycan glucosylation as a signal that promotes ER lectins-driven segregation of misfolded proteins in ER subdomains that are eventually delivered to endolysosomal compartments for ER-to-Lysosome-Associated Degradation (ERLAD). Here we show that the polymerization-prone Portland variant of Neuroserpin (NS_PL) associated with familial encephalopathy with NS inclusion bodies (FENIB) is a client of the ERLAD machinery. Its lysosomal clearance relies on the LC3-dependent delivery branch of ERLAD involving the lectin chaperone Calnexin (CNX), the ERphagy receptor FAM134B and the SNARE protein Syntaxin17 (STX17), which is engaged upon persistent glucosylation of the NS_PL oligosaccharide linked at the asparagine residue at position 321.

Keywords:  Conformational disease; ERLAD; ERphagy; N-glycosylation; Neuroserpin

DOI:  https://doi.org/10.1080/27694127.2026.2712797
Mech Ageing Dev. 2026 Aug 11. pii: S0047-6374(26)00087-4. [Epub ahead of print]233 112235

Epigenetic drift and LINE-1 activation in aging brain: Implications for neurodegenerative disease.

Alkinoos A Armoundas, Christina Piperi.

  Brain aging and age-associated neurological diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS), are largely attributed to epigenetic drift which is characterized by the gradual accumulation of alterations in neural cell methylation patterns over time. These methylation changes are particularly evident in transposable element (TE)-derived sequences such as Long interspersed element-1 (LINE-1) which comprises approximately 17% of the human genome. During aging, LINE-1 elements gradually lose their methylation, as well as the regulatory safeguard mechanisms that usually keep them inactive. This repression loss can lead to LINE-1 reactivation, contributing to harmful effects including genomic instability, neuroinflammation, and more. Together these findings indicate that impaired epigenetic maintenance, especially in repetitive genome regions, plays a key role in biological aging of neurons and glial cells. In this narrative review, we discuss the methylation dynamics and regulatory mechanisms of LINE-1 retrotransposons, their activation processes during aging, and contribution to age-associated neurological diseases. We also highlight the potential of targeting LINE-1 methylation to restore methylation homeostasis, epigenetic stability and delay brain aging.

Keywords:  Age-associated neurological diseases; Brain aging; Epigenetics; LINE-1

DOI:  https://doi.org/10.1016/j.mad.2026.112235
J Med Chem. 2026 Aug 13. 69(15): 19451-19481

Selective Brain-Penetrant TTBK1 Inhibitors Modulate TDP-43 Pathology and Rescue Cognitive Deficits in a Mouse Model of TDP-43 Proteinopathy.

Cecilia Sanchez-Santos, Alberto Jimenez-Amor, Loreto Martinez-Gonzalez, Vanesa Nozal, Raquel Martin-Morales, Elnaz Aledavood, Daniel Bausela, Kayla Merrigan, Karen Diaz-Palacios, Rezart Zhubi, Stefan Knapp, Francesc R Garcia-Gonzalo, Carmen Rodriguez-Cueto, Carmen Gil, Eva de Lago, Ana Martinez.

Transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological hallmark of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Modulation of TDP-43 pathology represents a promising disease-modifying strategy. Tau tubulin kinase 1 (TTBK1) has emerged as a relevant therapeutic target; however, selectivity over the TTBK2 isoform is required to avoid ciliogenesis-related liabilities. Here, we report the discovery of selective, brain-penetrant TTBK1 inhibitors through a structure-guided medicinal chemistry program. Lead compounds exhibit potent and selective TTBK1 inhibition, no impact on ciliogenesis, and central nervous system exposure. We found that these inhibitors reduce TDP-43 phosphorylation levels in neuroblastoma cells and FTD patient-derived models. The optimized lead compound demonstrated a brain-to-plasma ratio of 3:1, a maximum tolerated dose, and a wide therapeutic window. In vivo, administration restored cognitive deficits, conferred neuroprotection in the frontal cortex, and reduced microglial activation in an FTD-TDP mouse model, supporting its therapeutic potential.

DOI: https://doi.org/10.1021/acs.jmedchem.6c01882
Chem Sci. 2026 Aug 12.

Exploring viscosity sensitivity of π-extended coumarin fluorogen-based PRPGs for precise photorelease of valproic acid: detection and defibrillation of TDP-43 aggregation.

Subham Pal, Sagarika Das, Suchhanda Biswas, Sri Dinesh Murugan, Nihar Ranjan Jana, Asoke Prasun Chattopadhyay, N D Pradeep Singh.

Alteration of cellular microenvironment viscosity by protein aggregation plays a crucial role as a biophysical parameter that reflects abnormal cellular behaviour, leading to neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), etc. Herein, we report the design and development of a series of coumarin fluorogen-based photoremovable protecting groups (PRPGs, 5a-d) with variations in substitutions tethered with a π-extended linker that integrate viscosity sensing with visible-light-triggered release of bioactive molecules. By introducing π-extended conjugation and systematic substitution, the coumarin fluorogen-based PRPGs exhibit twisted intramolecular charge transfer (TICT)-based fluorescence modulation in response to microenvironmental viscosity. Comprehensive photophysical and photochemical investigations, supported by theoretical calculations, identified PRPG 5d as the most sensitive viscosity-responsive system with green-light absorption. Under viscous conditions, restricted bond rotation suppresses nonradiative decay and photoisomerization, enabling efficient photorelease of the neuroprotective agent valproic acid. The versatility of PRPG 5d was demonstrated in biologically relevant in vitro models, including TDP-43 protein aggregation and Parkinson's disease induced SH-SY5Y neuroblastoma cells. In both extracellular and intracellular neurodegenerative environments, increased viscosity was effectively sensed, triggering light-mediated valproic acid release and subsequent defibrillation. Overall, this work establishes coumarin fluorogen-based PRPGs as a promising platform for viscosity-guided, spatiotemporally controlled drug release, offering potential applications in the diagnosis and targeted therapy of neurodegenerative diseases.

DOI: https://doi.org/10.1039/d6sc03258c
Nat Commun. 2026 Aug 12. pii: 8088. [Epub ahead of print]17(1):

Photostimulation improves maturation of human photoreceptors.

Canan Celiker, Eva Hruba, Konstantina Kyriakou, Birthe Dorgau, Francisco Molina Gambin, Kamila Weissova, Edwin van Oosten, Lucie Englmaier, Nadezda Vaskovicova, Michael A Savage, Gerrit Hilgen, Evelyne Sernagor, Alejandro Garanto, Majlinda Lako, Tomas Barta.

The human retina contains photoreceptor cells that detect light and enable vision. The development of these cells involves a tightly regulated cascade of structural and molecular events, and their dysfunction leads to irreversible blindness in many retinal diseases. Human retinal organoids derived from stem cells have become powerful tools to model retinal development and disease, but they often remain immature and lack key features required for full function. Light is not only the sensory target of photoreceptors but also an important developmental signal in vivo. However, light has rarely been used as a deliberate stimulus during in vitro differentiation. Here we show that exposing retinal organoids to rhythmic light flickering at a specific frequency enhances photoreceptor maturation across multiple levels. This stimulation improves formation of presumptive outer segments, promotes transcriptional shifts from precursor toward more mature photoreceptor states, and is associated with enhanced responsiveness of downstream retinal neurons. These findings identify patterned light as a potent and physiologically relevant signal for driving retinal differentiation in vitro. This approach represents a non-invasive and easily scalable method for improving the quality of retinal organoids, with implications for disease modelling, drug discovery and the preparation of photoreceptors for cell-based therapies.

DOI: https://doi.org/10.1038/s41467-026-76112-3
Autophagy. 2026 Aug 12. 1-3

New insights into the molecular regulation of bridge-like lipid transfer proteins revealed by the Atg2-Atg18 structure.

Sabrina Chumpen Ramirez, Dmitry Shvarev, Fulvio Reggiori, Christian Ungermann.

  Atg9-Atg2-Atg18 complexes are essential for the biogenesis of the autophagosome as they mediate the elongation of the phagophore, the precursor structure of autophagosomes. This event occurs by the transfer of lipids through a membrane contact site (MCS) between the phagophore and the endoplasmic reticulum exit sites (ERES). The bridge-like lipid-transfer protein (BLTP) Atg2 interacts with the Atg9 and phosphatidylinositol-3-phosphate (PtdIns3P) on the phagophore and acts as a tether to establish this MCS. While not essential to form the phagophore-ERES MCS, Atg18 plays a crucial role in the phagophore elongation by stimulating Atg2 lipid transfer activity, based on in vitro experiments. To understand the molecular basis of this regulation, we recently solved the structure of the yeast Atg2-Atg18 complex using cryo-electron microscopy (cryo-EM) and identified the critical region in Atg2 required for the Atg2-Atg18 complex formation. Importantly, we applied structure-function analyses to unveil the molecular mechanism behind the Atg18-mediated stimulation of Atg2. We showed that Atg18 binding to Atg2 induces a structural repositioning of the hydrophobic cavity of Atg2 toward the membrane, which allows efficient transfer of lipids from the endoplasmic reticulum to the phagophore. Here, we summarize our recent work and extend our discussion on the molecular regulation of the lipid transfer activity, highlighting open questions concerning the function of the Atg9-Atg2-Atg18 module in the phagophore-ERES MCS.Abbreviations: ATG, autophagy related; BLTP, bridge-like lipid-transfer protein; cryo-EM, cryo-electron microscopy; ER, endoplasmic reticulum; ERES, ER exit sites; MCS, membrane contact site; PAS, phagophore assembly site; PtdIns3P, phosphatidylinositol-3-phosphate; TRAPPIII, transport protein particle III.

Keywords:  Atg18; Atg2; Atg9; autophagy; lipid transfer; phosphatidylinositol-3-phosphate

DOI:  https://doi.org/10.1080/15548627.2026.2716596
Autophagy Rep. 2026 ;5(1): 2710457

Retinal ganglion cell autophagy: a housekeeper essential for neuronal homeostasis and survival.

Yogapriya Sundaresan, Gulab S Zode.

  Retinal ganglion cells (RGCs) are the sole projection neurons of the retina and the only direct link between retinal circuitry and the brain. Maintaining this lifelong connection requires constitutive autophagy to preserve organelle quality control and neuronal homeostasis. Although autophagy has been widely studied following ocular hypertension and optic nerve injury, its physiological role in healthy RGCs has remained unclear. We have recently revealed that basal autophagy is highly active in RGCs and that conditional deletion of Atg5 or Atg7 is sufficient to induce progressive RGC dysfunction, optic nerve degeneration, and neurodegeneration. Autophagy deficiency caused the accumulation of swollen mitochondria, distended endoplasmic reticulum, fragmented Golgi, synaptic vesicles, and incomplete autophagosomes accompanied by increased p62 and LC3B levels. These findings establish basal autophagy as an essential housekeeping mechanism that preserves organelle quality control and long-term RGC integrity.

Keywords:  ATG5; ATG7; autophagy; conditional knockout; neurodegeneration; neuronal homeostasis; organelle accumulation; retinal ganglion cells

DOI:  https://doi.org/10.1080/27694127.2026.2710457
Front Cell Neurosci. 2026 ;20 1906023

Neurogenesis defects in iPSC-derived midbrain organoids of early-onset Parkinson's disease with 22q11.2 deletion syndrome.

Syugo Ueki, Toshiya Kimura, Rie Tohge, Atsushi Tamada, Mitsuaki Oki, Yusuke Yakushiji, Haruhisa Inoue, Satoshi Kaneko, Keiko Muguruma.

  Sporadic Parkinson's disease (PD) is typically a late-onset disorder caused by a combination of genetics, environment, and aging, manifesting when the loss of midbrain dopaminergic neurons exceeds a critical threshold, usually after the age of 50. Conversely, early-onset PD, as observed in cases linked to parkin (PRKN) gene mutations, suggests mechanisms involving either accelerated postnatal neuron loss or an insufficient number of neurons at birth. Patients with the 22q11.2 deletion syndrome (DS) have a significantly higher prevalence of early-onset PD. The absence of known genes associated with hereditary PD in the deleted region suggests the involvement of novel, non-traditional risk factors. This could potentially implicate the neurodevelopmental origin of dopaminergic neurons arising from the floor plate. To investigate this hypothesis, we generated midbrain organoids from induced pluripotent stem cells derived from a patient with 22q11.2 DS. The organoids recapitulated key aspects of in vivo neurogenesis, revealing enhanced differentiation of dopaminergic neurons in 22q11.2DS- and PRKN-derived organoids compared to controls on days 28 and 56 of culture. These findings suggest that, in early-onset PD patients with 22q11.2 DS or PRKN mutation, enhanced neurogenesis could result in reduced number of dopaminergic neurons during early development. The organoids of early-onset PD demonstrated that progenitors undergo enhanced differentiation at an early stage. This suggests that the atypical developmental process could reduce progenitors before there are enough mature dopaminergic neurons. This in turn indicates that the onset of PD may occur as early as the embryonic stage.

Keywords:  22q11.2 deletion syndrome; Parkinson's disease; dopaminergic neuron; floor plate; induced pluripotent stem cells; midbrain organoid

DOI:  https://doi.org/10.3389/fncel.2026.1906023
J Cell Mol Med. 2026 Aug;30(15): e71315

PRKCD Orchestrates Sevoflurane-Induced Cognitive Dysfunction in Aged Rats by Regulating PINK1/PRKN Mitophagy Pathway.

Yang Yu, Wei Zhang, Yingying Zhao, Yue Zhang, Pingle Li, Zepeng He.

  Post-operative cognitive dysfunction (POCD) is a cognitive disorder characterized by a decline in cognitive function following surgical procedures, with mitophagy identified as a significant underlying mechanism. Protein kinase C delta (PRKCD), localized within the mitochondria, is implicated in the regulation of PINK1/PRKN mitophagy pathway; however, the potential regulatory role of PRKCD in POCD through this pathway remains to be elucidated. Neurons and rats were exposed to sevoflurane (SEV) to illuminate the function and mechanism of PRKCD in POCD. Various methodologies were employed, including immunofluorescence, quantitative real-time PCR, CCK-8 assays, mitochondrial membrane potential (MMP) assessments, MitoSOX generation detection, Seahorse metabolic flux analysis, co-immunoprecipitation, western blotting and behavioural experiments like Morris water maze, novel object recognition and fear conditioning, along with haematoxylin and eosin and immunohistochemical staining. PRKCD was expressed in neurons and that SEV administration led to an upregulation of PRKCD expression. Furthermore, interference with PRKCD was found to restore cell viability in SEV-treated neurons. Additionally, inhibition of PRKCD resulted in the recovery of LC3 expression and the normalization of p62 levels in neurons subjected to SEV treatment. Suppressing PRKCD restored MMP and OCR, reduced MitoSOX in SEV-affected neurons and interacted with PRKN and PINK1, decreasing their expression. Overexpressing PRKN mitigated PRKCD inhibition's impact on mitochondrial damage. In vivo, SEV increased PRKCD, PINK1 and PRKN levels, but PRKCD knockdown improved behavioural and pathological outcomes, reversing changes in LC3-II, PINK1, PRKN and p62 expression. PRKCD enhanced SEV-induced POCD in aged rats via the regulation of PINK1/PRKN mitophagy pathway.

Keywords:  PRKCD; PRKN; mitophagy; post‐operative cognitive dysfunction; sevoflurane

DOI:  https://doi.org/10.1111/jcmm.71315
FEBS J. 2026 Aug 14.

A live-cell autophagy reporter reveals reversible vacuolation in naked mole-rat skin fibroblasts under lysosomal stress.

Fangze Tong, Mateo P Hoare, Laura J Grundy, Filomena Gallo, Karin H Müller, Ewan St John Smith, Janet R Kumita.

  Naked mole-rats (NMRs, Heterocephalus glaber) display unusual longevity and resistance to age-related decline, and accumulating evidence suggests that their autophagy-lysosome pathway (ALP) is regulated differently from that of conventional mammalian models. However, most studies in NMR cells have relied on static biochemical or ultrastructural readouts, leaving the dynamic organisation of autophagy in living cells poorly defined. Here, we establish a stable tandem fluorescent autophagy reporter in NMR skin fibroblasts using an mCherry-EGFP-LC3NMR construct to enable live-cell, single-cell resolution analysis of ALP dynamics. Under basal conditions, NMR skin fibroblasts exhibit a greater abundance of LC3-positive structures than HeLa cells, together with a mixed population of autophagosomes and autolysosomes, indicating a distinct steady-state organisation of the ALP. Chloroquine (CQ)-induced lysosomal stress caused the expected accumulation of LC3-positive structures but also triggered the formation of large cytoplasmic vacuoles in NMR skin fibroblasts. Importantly, this vacuolation was not associated with acute cytotoxicity and progressively resolved following CQ removal, accompanied by reorganisation of LC3-positive compartments and recovery of lysosomal acidity. Electron microscopy showed that CQ-induced vacuoles are membrane-bound, containing internal material and co-existing with multiple ALP-related vesicular compartments. Primary NMR skin fibroblasts display a similar vacuolation phenotype, indicating that this response is not an artefact of immortalisation or reporter expression. Together, these findings establish a live-cell platform for analysing autophagy in NMR cells and identify a distinctive, reversible vacuolation response to lysosomal stress, consistent with dynamic remodelling of the lysosomal system within NMR skin fibroblasts.

Keywords:  LC3‐reporter; autophagy–lysosome pathway; long‐lived species; naked mole‐rats; vacuolation

DOI:  https://doi.org/10.1111/febs.70695
Proc Natl Acad Sci U S A. 2026 Aug 18. 123(33): e2619147123

A quantitative model of a phenotypically variable genetic defect.

Alison G Simpkins, Dominic J Skinner, Brox Felix, Robert A Marmion, Jodi Schottenfeld-Roames, Stanislav Y Shvartsman.

  Phenotypic variability is a hallmark of human disease. It results from a combination of genetic modifiers, environment, and stochastic effects, but their contributions are hard to disentangle. Here, we establish the specification of terminal cells in the Drosophila tracheal system as a model for phenotypic variability and phenotypic emergence in Mendelian disorders. By perturbing Fibroblast growth factor (FGF) ligand dosage, which leads to a loss of terminal cells, we find that both microenvironmental and stochastic effects contribute to variability in terminal cell specification. We demonstrate that the phenotype results from reduced Ras-ERK signaling and use live imaging to identify molecular and morphological features of successful and failed terminal cell specification. Finally, using liability-threshold modeling, we quantify the relative magnitudes of genetic perturbations, microenvironmental effects, and stochasticity, establishing a strategy for dissecting the origins of phenotypic variability.

Keywords:  Drosophila trachea; FGF signaling; phenotypic variability

DOI:  https://doi.org/10.1073/pnas.2619147123
Front Neurol. 2026 ;17 1924943

α-Synuclein burden amplification in Parkinson's disease: a unified genetic, molecular, and cellular framework.

Sachiko Noda, Nobutaka Hattori.

   Introduction: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized pathologically by the accumulation and propagation of α-synuclein (α-syn). Although α-syn aggregation is considered central to PD pathogenesis, increasing evidence suggests that α-syn abundance may be as important as its conformational state. Genetic studies have demonstrated an SNCA dosage effect, with gene duplication and triplication associated with progressively more severe familial PD phenotypes. Complementary evidence indicates that dysfunction of protein clearance pathways, particularly the autophagy-lysosome system, promotes intracellular α-syn accumulation and increases its neurotoxic potential. In this review, we propose α-syn multiplication as an integrative framework for interpreting PD pathogenesis. This concept extends beyond SNCA copy-number variation to encompass processes that increase the effective α-syn burden within neurons or across neural networks, including increased gene expression, impaired degradation, disrupted proteostasis, and pathological propagation.
Methods: We summarize α-syn structural dynamics and the concentration-dependent distribution of monomeric, oligomeric, and fibrillar species. We then review evidence from SNCA gene-dosage studies and examine the role of the autophagy-lysosome pathway in regulating α-syn homeostasis, with particular emphasis on recent experimental findings demonstrating that autophagy deficiency exacerbates α-syn accumulation and neurodegeneration in human α-syn bacterial artificial chromosome transgenic mice.
Results: Collectively, the available genetic, biochemical, and experimental evidence supports a model in which the balance between α-syn production and clearance influences disease progression alongside protein misfolding. The interaction between increased protein burden and impaired clearance capacity provides a unifying mechanism linking familial and sporadic forms of PD.
Discussion: We propose that α-syn multiplication offers an integrative framework for understanding PD pathogenesis, provides a quantitative perspective on disease heterogeneity, and highlights therapeutic opportunities aimed at reducing α-syn burden and restoring proteostatic balance.

Keywords:  Parkinson’s disease; SNCA; autophagy–α-synuclein homeostasis; neurodegeneration; protein aggregation; α-synuclein

DOI:  https://doi.org/10.3389/fneur.2026.1924943