bims-axbals 2025-09-14 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2025–09–14
27 papers selected by
TJ Krzystek

Antibody targeting TDP-43 mitigates pathogenic pathways induced by the cerebrospinal fluid of ALS.
Excitatory cortical neurons from CDKL5 deficiency disorder patient-derived organoids show early hyperexcitability not identified in neurogenin2 induced neurons.
Modeling human retinal ganglion cell axonal outgrowth, development, and pathology using pluripotent stem cell-based microfluidic platforms.
Emerging Molecular Targets in Neurodegenerative Disorders: New Avenues for Therapeutic Intervention.
Caffeine mitigates ROS accumulation and attenuates motor neuron degeneration in the wobbler mouse model of amyotrophic lateral sclerosis.
Identification of p38 MAPK inhibition as a neuroprotective strategy for combinatorial SMA therapy.
Microglia contribute to bipolar depression through Serinc2-dependent phospholipid synthesis.
Presenilin loss impairs synaptic transmission and causes axonal degeneration through ryanodine receptor dysfunction, independent of γ-secretase activity.
The emergence of electrical activity in human brain organoids.
3D bioprinted human iPSC-derived neural progenitor cells as a novel platform for studying neurogenic niche.
Targeting protein misfolding in Alzheimer's disease: The emerging role of molecular chaperones.
An iPSC-derived neuronal model reveals manganese's role in neuronal endocytosis, calcium flux and mitochondrial bioenergetics.
α-Synuclein aggregates inhibit ESCRT-III through sequestration and collateral degradation.
Assessing mitochondrial number and morphology in a C. elegans model of human tauopathy.
Crystal structures of distinct parallel and antiparallel DNA G-quadruplexes reveal structural polymorphism in C9orf72 G4C2 repeats.
PI(3)P coordinates SNX17- and SNX27-dependent protein recycling for long-term synaptic plasticity.
Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer's patient-derived cortical neurons.
A single-cell, long-read, isoform-resolved case-control study of FTD reveals cell-type-specific and broad splicing dysregulation in human brain.
Novel small molecule derivatives improve survivability in the cellular model of Huntington's disease via improving mitochondrial fusion.
Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.
Ca2+ Fluxes across Membrane Contact Sites.
Fe3+ and H+-triggered "Turn-on" Fluorescence Probe Based on Lysosomal-targeted RBH-EdC for Monitoring Intragastric Acidity.
Membranes as targets and modifiers of mutant huntingtin aggregation.
SEPTIN9 locally activates the RhoGEF ARHGEF18 to promote early stages of mitochondrial fission.
Neurite branching is associated with mixed microtubule polarity in sea anemone neurons.
Steering Axon Development: Glial Cell Mechanisms in Drosophila.
Glioblastoma Cells Induce Neuron Loss In Vivo and In Vitro.

Neurotherapeutics. 2025 Sep 11. pii: S1878-7479(25)00215-6. [Epub ahead of print] e00737

Antibody targeting TDP-43 mitigates pathogenic pathways induced by the cerebrospinal fluid of ALS.

Amélie Poulin-Brière, Silvia Pozzi, Jean-Pierre Julien.

  Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the cytoplasmic mislocalization and accumulation of TAR DNA binding protein 43 (TDP-43). We reported previously the protective effects in a transgenic mouse model expressing ALS-linked mutant TDP-43A315T of a monoclonal antibody, called E6, binding specifically to the RNA Recognition Motif 1 (RRM1) domain of TDP-43. Here, we tested the effects of E6 antibody in an animal model of sporadic ALS based on the intracerebroventricular (i.c.v.) infusion during 14 days of cerebrospinal fluid (CSF) from sporadic ALS patients into transgenic mice expressing human TDP-43WT. Either intrathecal (i.t.) or i.c.v. injection of E6 antibody conferred protective effects in this model of disease. Thus, the CSF-inoculated E6 antibody reduced motor and cognitive impairments, mitigated TDP-43 proteinopathy and prevented neurofilament (Nf) disorganization in cortical and spinal neurons. Administration of E6 antibody reduced the loss of motor neurons in the spinal cord and the denervation of neuromuscular junctions. Moreover, E6 antibody promoted a switch toward features associated with a protective phenotype of microglial activation characterized by enhanced phagocytic function and reduced secretion of pro-inflammatory cytokines. The results suggest that an immunotherapy targeting the RRM1 domain of TDP-43 may confer protection against pathogenic pathways triggered by the CSF of ALS patients.

Keywords:  Antibody; CSF; Sporadic ALS; TDP-43; Therapy

DOI:  https://doi.org/10.1016/j.neurot.2025.e00737
Neurobiol Dis. 2025 Sep 08. pii: S0969-9961(25)00310-9. [Epub ahead of print] 107093

Excitatory cortical neurons from CDKL5 deficiency disorder patient-derived organoids show early hyperexcitability not identified in neurogenin2 induced neurons.

Madison R Glass, Dosh Whye, Nickesha C Anderson, Delaney Wood, Nina R Makhortova, Taryn Polanco, Kristina H Kim, Kathleen E Donovan, Gayathri Rajaram Srinivasan, Lorenzo Vaccaro, Ashish Jain, Davide Cacchiarelli, Liang Sun, Heather Olson, Elizabeth D Buttermore, Mustafa Sahin.

  CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy resulting from variants in cyclin-dependent kinase-like 5 (CDKL5) that lead to impaired kinase activity or loss of function. CDD is one of the most common genetic etiologies identified in epilepsy cohorts. To study how CDKL5 variants impact human neuronal activity, gene expression and morphology, CDD patient-derived induced pluripotent stem cells and their isogenic controls were differentiated into excitatory neurons using either an NGN2 induction protocol or a guided cortical organoid differentiation. Patient-derived neurons from both differentiation paradigms had decreased phosphorylated EB2, a known molecular target of CDKL5. Induced neurons showed no detectable differences between cases and isogenic controls in network activity using a multielectrode array, or in MAP2+ neurite length, and only two genes were differentially expressed. However, patient-derived neurons from the organoid differentiation showed increased synchrony and weighted mean firing rate on the multielectrode array within the first month of network maturation. CDD patient-derived cortical neurons had lower expression of CDKL5 and HS3ST1, which may change the extracellular matrix around the synapse and contribute to hyperexcitability. Similar to the induced neurons, there were no differences in neurite length across or within patient-control cell lines. Induced neurons have poor cortical specification while the organoid derived neurons expressed cortical markers, suggesting that the changes in neuronal excitability and gene expression are specific to cortical excitatory neurons. Examining molecular mechanisms of early hyperexcitability in cortical neurons is a promising avenue for identification of CDD therapeutics.

Keywords:  CDKL5; Cortical organoid; Encephalopathy; Hyperexcitability; Induced neurons; iPSC

DOI:  https://doi.org/10.1016/j.nbd.2025.107093
Proc Natl Acad Sci U S A. 2025 Sep 16. 122(37): e2423682122

Modeling human retinal ganglion cell axonal outgrowth, development, and pathology using pluripotent stem cell-based microfluidic platforms.

Cátia Gomes, Kang-Chieh Huang, Sailee S Lavekar, Jade Harkin, Carson G Prosser, Yue Fang, Claire Kalem, Adrian Oblak, Chi Zhang, Jason S Meyer.

  Retinal ganglion cells (RGCs) are highly compartmentalized neurons whose long axons serve as the sole connection between the eye and the brain. In both injury and disease, RGC degeneration occurs in a similarly compartmentalized manner, with distinct molecular and cellular responses in the axonal and somatodendritic regions. The goal of this study was to establish a microfluidic-based platform to investigate RGC compartmentalization in both health and disease states. Human pluripotent stem cell (hPSC)-derived RGCs were seeded into microfluidic devices that allow physical separation of axons from the somatodendritic compartment, enabling precise study of each region. Initial experiments characterized axonal outgrowth and the specific segregation of axons and dendrites. We then examined compartment-specific phenotypes in RGCs carrying the OPTN(E50K) glaucoma mutation compared to isogenic controls, including differences in axonal growth and axonal transport efficiency, with OPTN-mutant RGCs showing reduced axon length and slower transport, hallmarks of neurodegeneration. Axonal RNA-seq analyses revealed transcriptomic alterations related to disease states, including specific transcriptomic changes along OPTN axons. To assess glial influences on axonal health, we developed models with astrocytes localized specifically to the proximal axonal compartment and modulated their disease states to simulate pathological conditions. Importantly, the induction of diseased astrocytes solely along proximal axons triggered compartment-specific neurodegenerative changes in RGCs. Collectively, this platform represents a successful recapitulation of the spatially distinct features of hPSC-derived RGCs under both healthy and disease conditions, offering a physiologically relevant, human-specific in vitro system to study neuronal development, axon-glia interactions, and mechanisms underlying neurodegeneration.

Keywords:  axon; glaucoma; microfluidic; retinal ganglion cell; stem cell

DOI:  https://doi.org/10.1073/pnas.2423682122
Basic Clin Pharmacol Toxicol. 2025 Oct;137(4): e70107

Emerging Molecular Targets in Neurodegenerative Disorders: New Avenues for Therapeutic Intervention.

Ezgi Eroglu, Nusin Harmanci.

  Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and frontotemporal dementia represent a significant global health burden with limited therapeutic options. Current treatments are primarily symptomatic and fail to modify disease progression, emphasizing the urgent need for novel, mechanism-based interventions. Recent advances in molecular neuroscience have identified several non-classical pathogenic pathways, including neuroinflammation, mitochondrial dysfunction, impaired autophagy and proteostasis, synaptic degeneration and non-coding RNA dysregulation. In this focused review, we highlight emerging molecular targets such as TREM2, NLRP3, mTOR, TFEB, PINK1 and SIRT3, which offer promising avenues for therapeutic intervention. We also address challenges in target validation and translational drug development, while proposing future research directions that may facilitate the design of more effective treatments. A deeper understanding of these molecular mechanisms is essential for developing disease-modifying strategies to combat neurodegeneration.

Keywords:  Alzheimer's disease; autophagy; molecular targets; neurodegeneration; neuroinflammation

DOI:  https://doi.org/10.1111/bcpt.70107
Cell Commun Signal. 2025 Sep 10. 23(1): 394

Caffeine mitigates ROS accumulation and attenuates motor neuron degeneration in the wobbler mouse model of amyotrophic lateral sclerosis.

Aimo Samuel Christian Epplen, Maximilian Rothöft, Sarah Stahlke, Carsten Theiss, Veronika Matschke.

   BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by oxidative stress and progressive motor neuron degeneration. This study evaluates the potential neuroprotective effects of caffeine in the Wobbler mouse, an established model of ALS.
METHODS: Wobbler mice received caffeine supplementation (60 mg/kg/day) via drinking water, and key parameters, including muscle strength, NAD metabolism, oxidative stress, and motor neuron morphology, were assessed at critical disease stages.
RESULTS: Caffeine delayed motor performance decline, as observed in grip strength tests during the early symptomatic phase. Histological analyses revealed that significantly fewer motor neurons were lost in caffeine-treated mice at p41, despite no changes in soma morphology. Biochemical assays demonstrated that caffeine significantly reduced ROS levels and restored NAD levels to wildtype-like values, although NMNAT2 protein expression remained unaffected. The data suggest that caffeine mitigates oxidative stress through alternative pathways, potentially involving enhanced mitochondrial function and antioxidative defenses.
CONCLUSIONS: These findings highlight the potential of caffeine as a protective agent for delaying motor neuron degeneration in ALS. Future studies should explore optimal dosing strategies, combinatorial treatment approaches, and the underlying molecular mechanisms, to enable translation of these findings to human ALS patients.

Keywords:  ALS; Antioxidative defense; Muscle strength; NAD; Neurodegenerative disease; Reactive oxygen species (ROS)

DOI:  https://doi.org/10.1186/s12964-025-02415-5
EMBO Mol Med. 2025 Sep 08.

Identification of p38 MAPK inhibition as a neuroprotective strategy for combinatorial SMA therapy.

Maria J Carlini, Jorge Espinoza-Derout, Meaghan Van Alstyne, Sarah Tisdale, Eileen Workman, Marina K Triplett, Ivan Tattoli, Shubhi Yadav, Christopher E Henderson, D Martin Watterson, Livio Pellizzoni.

  Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by ubiquitous deficiency in the SMN protein. The identification of disease modifiers is key to understanding pathogenic mechanisms and broadening the range of targets for developing SMA therapies that complement SMN upregulation. Here, we report a cell-based screen that identified inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) as suppressors of proliferation defects induced by SMN deficiency in mouse fibroblasts. We further show that SMN deficiency induces p38 MAPK activation and that pharmacological inhibition of this pathway improves motor function in SMA mice through SMN-independent neuroprotective effects. Using a highly optimized p38 MAPK inhibitor (MW150) and combinatorial treatment in SMA mice, we observed synergistic enhancement of the phenotypic benefit induced by either MW150 or an SMN-inducing drug alone. By promoting motor neuron survival, pharmacological inhibition of p38 MAPK synergizes with SMN induction and enables enhanced synaptic rewiring of motor neurons within sensory-motor spinal circuits. These studies identify the p38 MAPK pathway as a therapeutic target and MW150 as a neuroprotective drug for combination therapy in SMA.

Keywords:  Combination Therapy; Neuroprotection; Spinal Muscular Atrophy (SMA); Survival Motor Neuron (SMN); p38 Mitogen-Activated Protein Kinase (p38 MAPK)

DOI:  https://doi.org/10.1038/s44321-025-00303-6
Proc Natl Acad Sci U S A. 2025 Sep 16. 122(37): e2500116122

Microglia contribute to bipolar depression through Serinc2-dependent phospholipid synthesis.

Ying-Han Wang, Chong-Lei Fu, Lin-Bo Chen, Chu-Yi Zhang, Jian-Shan Chen, Qiao-Ming Zhang, Yirui Liang, Rui-Lan Yang, Yu Li, Ya-Ni Zhang, Yi-Nuo Han, Zhen-Liang Yuan, Yi-Ni Chen, Haimei Li, Yanmeng Pan, Shaohua Hu, Ming Li, Li-Ping Cao, Jun Yao.

  Although clinical research has revealed microglia-related inflammatory and immune responses in bipolar disorder (BD) patient brains, it remains unclear how microglia contribute to the pathogenesis of BD. Here, we demonstrated that Serinc2 is associated with susceptibility to BD and showed a reduced expression in BDII patient plasma, which correlated with the disease severity. Using induced pluripotent stem cell (iPSC) models of sporadic and familial BDII patients, we found that Serinc2 expression showed deficits in iPSC-derived microglia-like cells, resulting in decreased synaptic pruning. Further, combining the microglia-specific Serinc2-deficient mouse and iPSC-microglia models, we found that microglial Serinc2 deficits functioned through attenuating the synthesis of serine-related phospholipids in the plasma membrane, thus resulting in depression-like behavioral abnormalities in the animals. Finally, we showed that the Serinc2-dependent lipid deficits diminished microglial membrane CR3 formation to interrupted synaptic pruning signals from neurons. Therefore, our results indicated that Serinc2 deficits in microglia might contribute to the pathogenesis of BD.

Keywords:  Serinc2; bipolar disorder; induced pluripotent stem cell; mental disorder; microglia

DOI:  https://doi.org/10.1073/pnas.2500116122
J Neurosci. 2025 Sep 09. pii: e1052252025. [Epub ahead of print]

Presenilin loss impairs synaptic transmission and causes axonal degeneration through ryanodine receptor dysfunction, independent of γ-secretase activity.

Xinran Du, Longgang Niu, Michal Ragan, Zuzanna Fracz, Zhao-Wen Wang.

Presenilin mutations are the most common cause of familial Alzheimer's disease (FAD), but the mechanisms by which they disrupt neuronal function remain unresolved, particularly in relation to γ-secretase activity. Using C. elegans, we show that the presenilin ortholog SEL-12 supports synaptic transmission and axonal integrity through a pathway involving the ryanodine receptor RYR-1. Loss-of-function mutations in either sel-12 or ryr-1 reduce neurotransmitter release and cause neuronal structural defects, with no additional impairment in double mutants, suggesting a shared pathway. Transgenic expression of a γ-secretase-inactive SEL-12 variant or human presenilin 1 restores normal synaptic transmission in sel-12 mutants. Notably, sel-12 loss does not alter ryr-1 transcript or protein levels. These findings define a novel γ-secretase-independent role for presenilin in maintaining neuronal function via ryanodine receptor signaling, providing new mechanistic insight into presenilin-linked neurodegeneration and pointing to potential therapeutic strategies for FAD.Significance Statement Mutations in presenilins are the major cause of familial Alzheimer's disease and are commonly associated with impaired synaptic transmission and neurodegeneration. However, the molecular mechanisms underlying these effects remain poorly understood. This study shows that loss of presenilin in C. elegans impairs neurotransmitter release and causes axonal degeneration through dysfunction of ryanodine receptors (RyRs), independent of presenilin's γ-secretase activity. Notably, RyR expression remains unchanged, suggesting that presenilins likely regulate RyR function. These findings uncover a γ-secretase-independent pathway linking presenilin dysfunction to synaptic and neuronal deficits. The findings of this study offer new insight into the pathogenesis of Alzheimer's disease.

DOI: https://doi.org/10.1523/JNEUROSCI.1052-25.2025
Stem Cell Reports. 2025 Sep 09. pii: S2213-6711(25)00236-X. [Epub ahead of print]20(9): 102632

The emergence of electrical activity in human brain organoids.

Sara Mancinelli, Sebastiano Bariselli, Simona Lodato.

  Human brain organoids, generated from pluripotent stem cells, recapitulate fundamental features of human brain development, including neuronal diversity, regional architecture, and functional network activity. Integrated multimodal and transcriptomic analyses reveal a molecular repertoire of ionotropic receptors supporting action potentials, synaptic transmission, and oscillatory dynamics resembling early brain activity. This review synthesizes current knowledge on the molecular and electrophysiological determinants of neuronal maturation and network computations, from synaptic integration to large-scale dynamics. Ongoing refinements in organoid generation are improving developmental timing and structural fidelity, establishing these models as powerful platforms for investigating brain differentiation, circuit formation, disease mechanisms, and biomedical applications.

Keywords:  brain organoids; electrical activity; membrane properties; network activity

DOI:  https://doi.org/10.1016/j.stemcr.2025.102632
APL Bioeng. 2025 Sep;9(3): 036116

3D bioprinted human iPSC-derived neural progenitor cells as a novel platform for studying neurogenic niche.

Lucas Simões Machado, Paula Scanavez Ferreira, Marina Rodrigues Pires, Larissa Valdemarin Bim, Natália Heloísa de Oliveira, Geisa Rodrigues Salles, Natalia Dall'Agnol Ferreira, Elisa Marozzi Cruz, Marimelia Aparecida Porcionatto.

Animal models, especially rodents, used to study neurodevelopment have significantly advanced our comprehension of cellular and molecular mechanisms. Nevertheless, differences in species-specific structures, gestation periods, and interneuronal connections limit animal models' ability to represent human neurodevelopment accurately. The unique characteristics of primate neural progenitor cells (NPCs) enable cortex expansion with gyrus formation, which does not occur in lissencephalic animals, like rodents. Therefore, there is a need for novel in vitro models using human cells that recapitulate the complexity of human brain development. Along with organoids, 3D bioprinting offers a platform for creating more complex in vitro models. We developed, extensively characterized, and successfully used a Geltrex™/GelMA hydrogel blend to bioprint human induced pluripotent stem cells-derived NPCs (hNPCs). We show that 3D bioprinted hNPCs can self-organize, revealing key features of a neurogenic niche, including proliferation, differentiation, and migration, remaining viable for over 110 days. Within the first 20 days, bioprinted constructs showed the formation of positive cell clusters for the neurogenic niche cell markers FABP7, NESTIN, and GFAP. Clusters were interconnected by process bundles supporting cell migration. The cells proliferated within the clusters, and over time, NPCs originated TUBB3+ neurons with long axonal tracts, prominent around the clusters. We propose this as a 4D model to study neurogenic niches' key cellular and molecular features in a 3D bioprinted scaffold, adding time as the fourth dimension. Neuronal maturation in this dynamic model recapitulates key neurogenic niche properties, making it suitable for neurodevelopmental disease modeling and drug screening.

DOI: https://doi.org/10.1063/5.0276704
Biomed Pharmacother. 2025 Sep 08. pii: S0753-3322(25)00725-5. [Epub ahead of print]191 118531

Targeting protein misfolding in Alzheimer's disease: The emerging role of molecular chaperones.

Anushka Sharma, Shriyansh Srivastava, Pranav Gupta, Sathvik Belagodu Sridhar, Mohd Tariq, G S N Koteswara Rao, Sachin Kumar, Tabarak Malik.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline and the accumulation of misfolded proteins, including amyloid-beta and hyperphosphorylated tau, which impair neuronal function and promote cell death. These misfolded proteins disrupt proteostasis by forming toxic aggregates that exacerbate disease progression. Molecular chaperones, such as heat shock proteins, actively maintain protein homeostasis by assisting in proper folding, preventing aggregation, and promoting the clearance of misfolded proteins. Dysfunction in chaperone systems contributes to the pathogenesis of AD, positioning them as promising therapeutic targets. Recent research has explored chaperone-based interventions, including small molecules, gene therapies, and autophagy and proteasomal degradation modulators, to restore protein balance. Advances in high-throughput screening and omics technologies have accelerated the identification of potential chaperone modulators. Despite these developments, the complexity of AD and the shortcomings of existing disease models make it difficult to translate preclinical results into successful clinical treatments. This review critically examines the role of protein misfolding and chaperone dysfunction in AD, evaluates emerging therapeutic strategies, and highlights current clinical trials, aiming to bridge molecular mechanisms with translational opportunities in the pursuit of novel AD treatments.

Keywords:  Alzheimer’s disease; Molecular chaperones; Protein homeostasis; Protein misfolding; Therapeutic strategies

DOI:  https://doi.org/10.1016/j.biopha.2025.118531
iScience. 2025 Sep 19. 28(9): 113311

An iPSC-derived neuronal model reveals manganese's role in neuronal endocytosis, calcium flux and mitochondrial bioenergetics.

Dimitri Budinger, Sharmin Alhaque, Ramón González-Méndez, Chris Dadswell, Katy Barwick, Arianna Ferrini, Charlotte Roth, Conor J McCann, Karin Tuschl, Fatma Al Jasmi, Maha S Zaki, Julien H Park, Russell C Dale, Shekeeb Mohammad, John Christodoulou, Dale Moulding, Michael R Duchen, Serena Barral, Manju A Kurian.

  Manganese (Mn) is an essential trace metal required for normal biological function, yet it also poses neurotoxic risks when dysregulated. Maintaining proper intracellular and extracellular Mn levels is critical, as Mn imbalance has been implicated in a spectrum of human diseases-including inherited Mn transport disorders, acquired manganism, and more prevalent neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Despite these associations, the cellular mechanisms driving Mn-induced neuropathology remain poorly understood. To investigate this, we developed an induced pluripotent stem cell (iPSC)-derived midbrain neuronal model using patient lines with mutations in SLC39A14, SLC39A8, and SLC30A10. Through integrated transcriptomic and functional analyses, we found that Mn dyshomeostasis disrupts essential neuronal pathways, including mitochondrial bioenergetics, calcium signaling, endocytosis, glycosylation, and stress responses-leading to early neurodegeneration. This humanized model advances our understanding of Mn's impact on neuronal health and disease and highlights potential molecular targets for future therapeutic interventions in Mn-related neurological disorders.

Keywords:  Cell biology; Molecular biology; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2025.113311
Mol Cell. 2025 Sep 10. pii: S1097-2765(25)00707-5. [Epub ahead of print]

α-Synuclein aggregates inhibit ESCRT-III through sequestration and collateral degradation.

Cole S Sitron, Victoria A Trinkaus, Ana Galesic, Maximilian Garhammer, Patricia Yuste-Checa, Ulrich Dransfeld, Dennis Feigenbutz, Jiuchun Zhang, Larysa Ivashko, Irina Dudanova, J Wade Harper, F Ulrich Hartl.

  α-Synuclein aggregation is a hallmark of Parkinson's disease and related synucleinopathies. Extracellular α-synuclein fibrils enter naive cells via endocytosis, followed by transit into the cytoplasm to seed endogenous α-synuclein aggregation. Intracellular aggregates sequester numerous proteins, including subunits of the endosomal sorting complexes required for transport (ESCRT)-III system for endolysosome membrane repair, but the toxic effects of these events remain poorly understood. Using cellular models and in vitro reconstitution, we found that α-synuclein fibrils interact with a conserved α-helix in ESCRT-III proteins. This interaction sequesters ESCRT-III subunits and triggers their proteasomal destruction in a process of "collateral degradation." These twin mechanisms deplete the available ESCRT-III pool, initiating a toxic feedback loop. The ensuing loss of ESCRT function compromises endolysosome membranes, thereby facilitating escape of aggregate seeds into the cytoplasm, facilitating a "second wave" of templated aggregation and ESCRT-III sequestration. We suggest that collateral degradation and the triggering of self-perpetuating systems are general mechanisms of sequestration-induced proteotoxicity.

Keywords:  CHMP2B; ESCRT; ESCRT-III; Parkinson’s disease; aggregation; lysosome; protein aggregate spreading; proteostasis; sequestration; α-synuclein

DOI:  https://doi.org/10.1016/j.molcel.2025.08.022
Methods Cell Biol. 2025 ;pii: S0091-679X(25)00130-X. [Epub ahead of print]197 275-290

Assessing mitochondrial number and morphology in a C. elegans model of human tauopathy.

Eleni Tsakiri, Giorgos Niforos-Garcia, Brian D Ackley, Konstantinos Palikaras.

  Mitochondrial dysfunction is a shared hallmark of neurodegenerative disorders, including Alzheimer's disease (AD) and tauopathies among others. Pathological alterations of the microtubule-associated protein Tau can disrupt mitochondrial dynamics, transport, and function, ultimately leading to neuronal toxicity and synaptic deficits. Understanding these processes is crucial for developing therapeutic interventions. The nematode Caenorhabditis elegans serves as a powerful model to study mitochondrial morphology and Tau-induced neurotoxicity due to its well-characterized nervous system and genetic tractability. Here, we describe a robust methodology for assessing mitochondrial morphology, Tau aggregation, and neuronal integrity in a nematode model of tauopathy. By combining confocal laser scanning microscopy and motility assays, we provide a comprehensive framework for investigating mitochondrial deficits. This approach offers valuable insights into the interplay between Tau pathology and mitochondrial dysfunction, thereby advancing our understanding of neurodegenerative mechanisms and potential therapeutic targets.

Keywords:  Alzheimer’s disease; Caenorhabditis elegans; Mitochondria; Motility; Neurodegeneration; Neurons; Tauopathy

DOI:  https://doi.org/10.1016/bs.mcb.2025.05.002
Nucleic Acids Res. 2025 Sep 05. pii: gkaf879. [Epub ahead of print]53(17):

Crystal structures of distinct parallel and antiparallel DNA G-quadruplexes reveal structural polymorphism in C9orf72 G4C2 repeats.

Yanyan Geng, Changdong Liu, Haitao Miao, Monica Ching Suen, Yuanyuan Xie, Bingchang Zhang, Wanhong Han, Caiming Wu, Haixia Ren, Xueqin Chen, Hwan-Ching Tai, Zhanxiang Wang, Guang Zhu, Qixu Cai.

The abnormal expansion of GGGGCC (G4C2) repeats in the noncoding region of the C9orf72 gene is a major genetic cause of two devastating neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These G4C2 repeats are known to form G-quadruplex (G4) structures, which are hypothesized to contribute to disease pathogenesis. Here, we demonstrated that four DNA G4C2 repeats can fold into two structurally distinct G4 conformations: a parallel and an antiparallel topology. The high-resolution crystal structure of the parallel G4 reveals an eight-layered dimeric assembly, formed by two identical monomeric units. Each unit contains four stacked G-tetrads connected by three propeller CC loops and is stabilized through 5'-to-5' π-π interactions and coordination with a central K+ ion. Notably, the 3'-ending cytosines form a C·C+·C·C+ quadruple base pair stacking onto the adjacent G-tetrad layer. In contrast, the antiparallel G4 adopts a four-layered monomeric structure with three edgewise loops, where the C6 and C18 bases engage in stacking interaction with neighboring G-tetrad via a K+ ion. These structurally distinct G-quadruplexes provide mechanistic insights into C9orf72-associated neurodegeneration and offer potential targets for the development of structure-based therapeutic strategies for ALS and FTD.

DOI: https://doi.org/10.1093/nar/gkaf879
J Cell Biol. 2025 Nov 03. pii: e202411198. [Epub ahead of print]224(11):

PI(3)P coordinates SNX17- and SNX27-dependent protein recycling for long-term synaptic plasticity.

Pilar Rivero-Ríos, Tunahan Uygun, Garrett D Chavis, Hankyu Lee, Bo Duan, Michael A Sutton, Lois S Weisman.

Two major protein recycling pathways have emerged as key regulators of enduring forms of synaptic plasticity, such as long-term potentiation (LTP), yet how these pathways are recruited during plasticity is unknown. Phosphatidylinositol-3-phosphate (PI(3)P) is a key regulator of endosomal trafficking and alterations in this lipid have been linked to neurodegeneration. Here, using primary hippocampal neurons, we demonstrate dynamic PI(3)P synthesis during chemical induction of LTP (cLTP), which drives coordinate recruitment of the SNX17-Retriever and SNX27-Retromer pathways to endosomes and synaptic sites. Both pathways are necessary for the cLTP-dependent structural enlargement of dendritic spines and act in parallel by recycling distinct sets of cell surface proteins at synapses. Importantly, preventing PI(3)P synthesis blocks synaptic recruitment of SNX17 and SNX27, decreases cargo recycling, and blocks LTP in cultured neurons and hippocampal slices. These findings provide mechanistic insights into the regulation of endocytic recycling at synapses and define a role for dynamic PI(3)P synthesis in synaptic plasticity.

DOI: https://doi.org/10.1083/jcb.202411198
Mol Psychiatry. 2025 Sep 08.

Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer's patient-derived cortical neurons.

Komal Saleem, Zichun Xiao, Binglin Zhu, Yong Ren, Zhen Yan, Jian Feng.

Hyperphosphorylation of Tau and the ensuing microtubule destabilization are linked to synaptic dysfunction in Alzheimer's disease (AD). We find a marked increase of phosphorylated Tau (pTau) in cortical neurons differentiated from induced pluripotent stem cells (iPSCs) of AD patients. It is accompanied by significantly elevated expression of Serum and Glucocorticoid-regulated Kinase-1 (SGK1), which is induced by cellular stress, and Histone Deacetylase 6 (HDAC6), which deacetylates tubulin to destabilize microtubules. Indeed, acetylated tubulin and microtubule stability are significantly lower in AD-derived cortical neurons. SGK1 inhibitors or shRNA decrease Tau phosphorylation and HDAC6 levels while increasing acetylated tubulin in AD neurons. Overexpression of SGK1 in normal neurons does the opposite. These results suggest that elevation of the cellular stress-induced SGK1 increases Tau phosphorylation and HDAC6 expression, which destabilize microtubules to compromise many cellular functions subserving cognition. The coordinated increases in SGK1, pTau, and HDAC6, as well as the corresponding decrease in acetylated tubulin and microtubule stability in AD neurons, offer attractive targets for therapeutic development.

DOI: https://doi.org/10.1038/s41380-025-03225-4
Cell Rep. 2025 Sep 05. pii: S2211-1247(25)00969-6. [Epub ahead of print]44(9): 116198

A single-cell, long-read, isoform-resolved case-control study of FTD reveals cell-type-specific and broad splicing dysregulation in human brain.

Natan Belchikov, Wen Hu, Li Fan, Anoushka Joglekar, Yi He, Careen Foord, Julien Jarroux, Justine Hsu, Shaun Pollard, Sadaf Amin, Andrey D Prjibelski, Shiaoching Gong, Sai Zhang, Roberta Giannelli, Harro Seelaar, Alexandru I Tomescu, M Elizabeth Ross, Alissa Nana Li, Lea T Grinberg, Salvatore Spina, Bruce L Miller, Johnathan Cooper-Knock, Michael P Snyder, William W Seeley, Priyanka Rao-Ruiz, Sabine Spijker, August B Smit, Claire D Clelland, Li Gan, Hagen U Tilgner.

  Progranulin-deficient frontotemporal dementia (GRN-FTD) is a major cause of familial FTD with TAR DNA-binding protein 43 (TDP-43) pathology, which is linked to exon dysregulation. However, little is known about this dysregulation in glial and neuronal cells. Here, using splice-junction-covering enrichment probes, we introduce single-nuclei long-read RNA sequencing 2 (SnISOr-Seq2), targeting 3,630 high-interest genes without loss of precision, and complete the first single-cell, long-read-resolved case-control study for neurodegeneration. Exons affected by FTD-associated skipping are shorter than those whose inclusion is increased. Up to 30% of cell-(sub)type-specific splicing dysregulation is masked by other cell types or cortical layers. Surprisingly, strong splicing dysregulation events can occur in select but not all cell types. In some cases, a cell type switches in FTD to the splicing pattern of a different cell type. In addition, in separate GRN-FTD samples, the more FTD-prone frontal cortex exhibits more FTD-associated splicing patterns than the occipital cortex. Our methodologies are widely applicable to brain and other diseases.

Keywords:  CP: Neuroscience; RNA isoform; TDP-43; frontotemporal dementia; frontotemporal lobar degeneration; long read; neurodegeneration; progranulin; single cell; single nucleus; splicing

DOI:  https://doi.org/10.1016/j.celrep.2025.116198
RSC Med Chem. 2025 Aug 01.

Novel small molecule derivatives improve survivability in the cellular model of Huntington's disease via improving mitochondrial fusion.

Pradeep Kodam, Vaishali Kumar, Paramita Pattanayak, Praharsh Vitta, Tanmay Chatterjee, Shuvadeep Maity.

Mitochondrial dysfunction is one of the primary cellular conditions involved in developing Huntington's disease (HD) pathophysiology. The accumulation of mutant huntingtin protein with abnormal PolyQ repeats resulted in the death of striatal neurons with enhanced mitochondrial fragmentation. In search of neuroprotective molecules against HD conditions, we synthesized a set of isoxazole-based small molecules to screen their suitability as beneficial chemicals improving mitochondrial health. Systematic characterization of one of these isoxazole derivatives, C-5, demonstrated improved mitochondrial health with reduced apoptosis via rebalancing fission-fusion dynamics in HD condition. Gene and protein expression analysis confirmed that C-5 treatment enhanced the expression of mitochondrial fusion regulators (MFN1/2) via transcriptional upregulation of PGC-1α, a transcriptional co-activator controlling mitochondrial biogenesis. Collectively, this novel fusion agonist can potentially become a new therapeutic alternative for treating PolyQ-mediated mitochondrial dysfunction, a hallmark of HD pathology.

DOI: https://doi.org/10.1039/d5md00345h
Autophagy. 2025 Sep 13.

Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.

Antonis Roussos, Katerina Kitopoulou, Fivos Borbolis, Christina Ploumi, Despoina D Gianniou, Zhiquan Li, Haijun He, Eleni Tsakiri, Helena Borland, Ioannis K Kostakis, Martina Samiotaki, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.

  Mitochondrial dysfunction and impaired mitophagy are hallmarks of aging and age-related pathologies. Disrupted inter-organellar communication among mitochondria, endoplasmic reticulum (ER), and lysosomes, further contributes to cellular dysfunction. While mitophagy has emerged as a promising target for neuroprotection and geroprotection, its potential to restore age-associated defects in organellar crosstalk remains unclear. Here, we show that mitophagy deficiency deregulates the morphology and homeostasis of mitochondria, ER and lysosomes, mirroring age-related alterations. In contrast, urolithin A (UA), a gut-derived metabolite and potent mitophagy inducer, restores inter-organellar communication via calcium signaling, thereby, promoting mitophagy, healthspan and longevity. Our multi-omic analyses reveal that UA reorganizes ER, mitochondrial and lysosomal networks, linking inter-organellar dynamics to mitochondrial quality control. In C. elegans, UA induces calcium release from the ER, enhances lysosomal activity, and drives DRP-1/DNM1L/DRP1-mediated mitochondrial fission, culminating in efficient mitophagy. Calcium chelation abolishes UA-induced mitophagy, blocking its beneficial impact on muscle function and lifespan, underscoring the critical role of calcium signaling in UA's geroprotective effects. Furthermore, UA-induced calcium elevation activates mitochondrial biogenesis via UNC-43/CAMK2D and SKN-1/NFE2L2/Nrf2 pathways, which are both essential for healthspan and lifespan extension. Similarly, in mammalian cells, UA increases intracellular calcium, enhances mitophagy and mitochondrial metabolism, and mitigates stress-induced senescence in a calcium-dependent manner. Our findings uncover a conserved mechanism by which UA-induced mitophagy restores inter-organellar communication, supporting cellular homeostasis and organismal health.

Keywords:  Calcium; ER; cellular senescence; geroprotection; lysosome; mitochondria

DOI:  https://doi.org/10.1080/15548627.2025.2561073
Cold Spring Harb Perspect Biol. 2025 Sep 09. pii: a041765. [Epub ahead of print]

Ca2+ Fluxes across Membrane Contact Sites.

Lucia Barazzuol, Marisa Brini, Tito Calì.

The calcium ion (Ca2+) is a pivotal second messenger orchestrating diverse cellular functions, including metabolism, signaling, and apoptosis. Membrane contact sites (MCSs) are critical hubs for Ca2+ exchange, enabling rapid and localized signaling across cell compartments. Well-characterized interfaces, such as those between the endoplasmic reticulum (ER) and mitochondria and ER-plasma membrane (PM), mediate Ca2+ flux through specialized channels. Less understood, yet significant, contacts involving Golgi, lysosomes, peroxisomes, and the nucleus further expand the landscape of intracellular Ca2+ signaling. These organelles are engaged in Ca2+ homeostasis mainly through their MCS, but the molecular players and the mechanisms regulating the process of Ca2+ transfer remain incompletely elucidated. This review provides a comprehensive overview of Ca2+ signaling across diverse MCS, emphasizing understudied organelles and the need for further investigation to uncover novel therapeutic opportunities.

DOI: https://doi.org/10.1101/cshperspect.a041765
Chemistry. 2025 Sep 08. e01717

Fe3+ and H+-triggered "Turn-on" Fluorescence Probe Based on Lysosomal-targeted RBH-EdC for Monitoring Intragastric Acidity.

Weiqing Xu, Linyu Zeng, Jiarong Nan, Weiran Ling, Hai Xiong.

  The long-term visualization of intracellular Fe3+ dynamics and lysosomal activity is crucial for investigating the physiological roles and functions of lysosomes during the growth of organisms. The lysosome-targeted fluorescent probe (RBH-EdC), derived from rhodamine-nucleoside conjugates, demonstrates a sophisticated dual-activation design: one is Fe3⁺ response, triggering spirolactam ring-opening to form xanthine structures, resulting in ≥ 1000-fold fluorescence enhancement with visible colorimetric transition (colorless→pink). Another is pH sensitivity, demonstrating protonation-dependent fluorescence amplification at the dC at site N3 (pKa = 2.9), achieving a 30-fold intensity increase at pH 2.5 within the 1.0-5.0 range. Remarkably, the RBH-EdC/Fe3⁺ complex showed a further significant 20-fold fluorescence enhancement at pH 3.0. This Fe3⁺/H⁺ co-activated "turn-on" system provides exceptional signal amplification for both in vitro and in vivo applications, enabling precise exploration of lysosome-related biological processes, including the response of the pH microenvironment, real-time monitoring of lysosomal pH dynamics, in situ measurement of gastric acidity levels, and potential application in gastric ulcer diagnostics.

Keywords:  Fe3+ detection; artifical nucleoside; lysosomal imaging; monitor and diagnosis; pH‐responsive; rhodamine sensor

DOI:  https://doi.org/10.1002/chem.202501717
Trends Biochem Sci. 2025 Sep 09. pii: S0968-0004(25)00194-X. [Epub ahead of print]

Membranes as targets and modifiers of mutant huntingtin aggregation.

Justin Legleiter.

  Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene, resulting in an expanded polyglutamine (polyQ) tract in HTT protein. Expanded polyQ tracts cause mutant HTT (mHTT) to aggregate and accumulate as cellular inclusions. Recent studies highlight the interactions between mHTT and different cellular membranes that contribute to HD pathogenesis. Beyond being targets for mHTT-induced damage, membranes modify mHTT aggregation in a complex manner. This review explores the membrane abnormalities observed in a variety of HD models and the interplay between binding to and subsequent aggregation of mHTT on membranes, with an emphasis on N-terminal mHTT fragments. Understanding mHTT-lipid interactions may provide potential targets for therapeutic intervention that would complement other efforts.

Keywords:  Huntington’s disease; amyloid; lipids; neurodegeneration; polyglutamine

DOI:  https://doi.org/10.1016/j.tibs.2025.08.005
J Cell Biol. 2025 Oct 06. pii: e202406017. [Epub ahead of print]224(10):

SEPTIN9 locally activates the RhoGEF ARHGEF18 to promote early stages of mitochondrial fission.

Rachel Shannon, Yadu Balachandran, Xindi Wang, Maxime Boutry, Hong Xie, Peter K Kim, William S Trimble.

Mitochondria continually undergo fission to maintain their network and health. Nascent fission sites are marked by the ER, which facilitates actin polymerization to drive calcium flux into the mitochondrion and constrict the inner mitochondrial membrane. Septins are a major eukaryotic cytoskeleton component that forms filaments that can both directly and indirectly modulate other cytoskeleton components, including actin. Septins have been implicated in mitochondrial fission; however, a connection between septins and the regulation of cytoskeletal machinery driving fission is not known. We find that SEPTIN9 is present at mitochondrial fission sites from its early stages with the ER and prior to the fission factor dynamin-related protein 1 (DRP1). SEPTIN9 has an isoform-specific role in fission, dependent on its N-terminal interaction to activate a Rho guanine nucleotide exchange factor, ARHGEF18. Without SEPTIN9, mitochondrial calcium influx is impaired, indicating SEPTIN9-containing octamers play a critical role in the early stages of fission.

DOI: https://doi.org/10.1083/jcb.202406017
J Exp Biol. 2025 Sep 11. pii: jeb.251169. [Epub ahead of print]

Neurite branching is associated with mixed microtubule polarity in sea anemone neurons.

Michelle C Stone, Gregory O Kothe, Timothy J Jegla, Melissa M Rolls.

  Bilaterian animals can make polarized neurons with functionally distinct dendrites and axons. A central aspect of this polarity is different arrangements of microtubules; axons have plus-end-out microtubules, while dendrites contain minus-end-out microtubules, allowing different sets of proteins and organelles to be trafficked to each. In cnidarians, neurons with multiple plus-end-out axon-like neurites have been described. To determine whether neurons with axo-dendritic polarity might exist in cnidarians, we surveyed neurons in the model sea anemone Nematostella vectensis. Microtubule polarity was assessed in mosaic animals expressing EB1-GFP, which binds to growing microtubule plus ends. Neurons were separated into general groups based on morphology. Neurons without any branching had predominantly plus-end-out microtubule polarity. Neurons with at least one neurite branch had significantly more minus-end-out microtubules, and neurons with more than one branch had over fifteen percent minus-end-out microtubules. To identify a population of neurons enriched for branching, we performed a promoter screen. We found that the Shal1 promoter labeled cnidocytes and neurons with branched neurites. In these cells about 30% of microtubules were minus-end-out, which is in the range described for vertebrate dendrites. Finally, we re-examined neurons broadly to identify cells that had both branched and unbranched neurites. When these cells had neurites with different polarities, it was typically the branched one that had mixed microtubules. Thus, in Nematostella, neurite branching is associated with more mixed microtubule polarity and our results also suggest that classically polarized neurons may exist in cnidarian animals.

Keywords:  Cnidarian; Microtubule polarity; Neuronal evolution; Neuronal polarity

DOI:  https://doi.org/10.1242/jeb.251169
ACS Chem Neurosci. 2025 Sep 07.

Steering Axon Development: Glial Cell Mechanisms in Drosophila.

Keyao Long, Erqian Huang, Yuhao Yuan, Su Wang, Menglong Rui.

  Glial cells play an indispensable role in the nervous system, providing structural support to neurons and regulating their function and development. Glia support neural network formation and plasticity in axon guidance, synaptic pruning, and neurogenesis. Of note, studies have shown that glial cell dysfunction is closely related to the occurrence of neurological diseases. An in-depth exploration of the multiple roles of glia helps reveal the mechanism of nervous system functioning and provides an important basis for novel therapeutic strategies. Drosophila melanogaster is one of the model organisms for studying glial function because of its relatively simple nervous system, but highly conserved function with mammals. Here, we summarize the studies of Drosophila glial cell roles in axon guidance, pruning, and regeneration, three key processes in axonal development, which aim to understand neuron-glia interactions, as well as provide novel insights into the molecular basis of neurodevelopment and associated neurological disorders.

Keywords:  axon guidance; axon pruning; axon regeneration; neurological disorders

DOI:  https://doi.org/10.1021/acschemneuro.5c00451
Cancers (Basel). 2025 Aug 28. pii: 2817. [Epub ahead of print]17(17):

Glioblastoma Cells Induce Neuron Loss In Vivo and In Vitro.

Komal N Rawal, Charlotte Degorre, Philip J Tofilon.

  Background: The vast majority of GBMs recur within 2 years following standard treatment, including radiotherapy. Seizures and epilepsy are common in GBM patients, suggesting tumor-cell-induced neuron toxicity. Additionally, the tumor cells and neurons interact during tumor development; however, the effects of tumor cells on the neurons remain unclear. Methods: Orthotopic xenografts initiated from GSCs expressing GFP implanted into the right striatum of nude mice were irradiated (10 Gy) 35 days after implantation, followed by immunohistochemistry (IHC) to investigate the tumor cell-neuron interactions. Moreover, we established a direct coculture of human GSCs and neurons differentiated from human iPSC-derived neural progenitor cells (NPCs) to investigate the impact of the tumor cells on the neurons. Neuronal cell counts were monitored to assess neurotoxicity. Culture CM were analyzed through cytokine profiling. Results: In untreated mice, tumors invaded across the right hemisphere (RH), with increased cell contact with the mouse neurons. In irradiated mice, the tumor regrowth was less invasive and had fewer neurons. In vitro, the GSCs induced neuronal death in the direct coculture. Similarly, the CM from the direct cocultures caused significant neuronal death. The cytokine analysis revealed that the cocultures uniquely secreted IL-8 into the CM. Furthermore, treatment with recombinant (r) human IL-8 caused significant neuron death, while IL-8 blocking antibodies prevented this neurotoxicity in the coculture. Conclusions: This study demonstrates that GBM tumors regrown after radiation lack neurons, and direct interaction between GSCs and the neurons is necessary for GSC-mediated neurotoxicity, likely involving IL-8 in neuronal death.

Keywords:  GSC–neuron coculture; Glioblastoma; Glioblastoma stem cells; Neuron differentiation; iPSC-derived Neuron Progenitor Cells; neuron death

DOI:  https://doi.org/10.3390/cancers17172817