bims-axbals 2026-10-18 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2026–10–18
27 papers selected by
TJ Krzystek

Motor Neuron Disease in a Dish: The Power of Human Induced Pluripotent Stem Cell-Derived Spinal Motor Neurons and Glial Cells.
Human iPSC-Derived Brain Cells, Organoids, and Organoids-on-Chips: Advancing Neurological Disease Modeling to Improve Clinical Outcome.
Isolated Axoplasm from Squid and Pathogenic Mechanisms in Amyotrophic Lateral Sclerosis.
Early life social isolation primes flies for more rapid TDP-43 dependent neurodegeneration later in life.
Integrative ALS therapy: gene targeted therapy by base editing and potential exercise rehabilitation as synergistic strategies for functional recovery.
The small giant actor in the pathogenesis of neurodegenerative diseases: Microtubules.
DNA methylation in motor neuron biology and epigeneticopathy in amyotrophic lateral sclerosis.
ALS/FTD-linked TDP-43 alterations prevent HSV-1 infection by disrupting cell-adhesion pathways.
Ataxin-2 downregulation rewires neuronal and astrocytic metabolism to protect against TDP-43 toxicity.
Modeling human neurodegeneration with iPSCs: opportunities, limitations, and the challenge of aging.
Membrane contact activation of Piezo2 drives lysosome-mitochondrion Ca2+ transfer and signaling in Trypanosoma cruzi.
Engineering Functional Skeletal Muscle Tissues from Human Induced Pluripotent Stem Cells.
Conformational allocation of mitofusin 2 in neuronal mitochondrial dynamics: Mechanisms and therapeutic targeting.
Disrupting Mitochondrial Homeostasis via TBC1D15 Protein.
Double periodicity of the AnkyrinG-associated complex in the axon initial segment.
Bulk Differentiation of Human Induced Pluripotent Stem Cells into Contractile Skeletal Muscles.
Leucine-rich repeat kinase 2 is involved in the microtubule-mediated regulation of intraocular pressure.
iPSC neurodegenerative disease initiative isogenic CAG repeat iPSC line for Huntington's disease.
Late endosome trafficking is slower in regenerated dendrites.
Extracellular Vesicle Isolation and Purification from Skeletal Muscle Cells.
CHCHD2 mitigates age-associated proteostatic collapse by maintaining homeostasis of the mitochondria-lysosome axis.
Local ROS and inefficient autophagosome formation limit Optineurin-mediated mitophagy in neurons.
Revisiting the muscle spindle in ALS: Implications for spinal motor network dysfunction.
Mapping high resolution, multidimensional phase diagrams of near-physiological protein condensates.
Mitofusin Activation Delays Aging in Caenorhabditis elegans.
MFN2-associated astrocyte dysfunction contributes to neuronal hyperexcitability and depressive-like behaviors.
Role of Miro1 in Mitochondrial Dysfunction and Neurodegeneration in Huntington's Disease.

Cells. 2026 Oct 01. pii: 1798. [Epub ahead of print]15(19):

Motor Neuron Disease in a Dish: The Power of Human Induced Pluripotent Stem Cell-Derived Spinal Motor Neurons and Glial Cells.

Martina Morrone, Chiara F Valori, Liliana Brambilla, Daniela Rossi.

  Induced pluripotent stem cells (iPSCs) have revolutionized disease modelling by providing unprecedented opportunities to investigate complex human disorders. Among others, Amyotrophic Lateral Sclerosis (ALS), the most common adult-onset motor neuron disease, clearly embodies this complexity. This disorder remains particularly challenging not only because of its marked clinical and molecular heterogeneity but also as a consequence of the composite interactions between motor neurons and the neighboring non-neuronal cells, especially astrocytes, which contribute to disease progression. The ability to generate patient-specific spinal motor neurons and astrocytes from human iPSCs has enabled the development of in vitro models that recapitulate key pathological features of ALS, offering valuable platforms to investigate disease mechanisms, to identify therapeutic targets, and to support personalized medicine approaches. In this review, we summarize current iPSC-based strategies for modelling ALS, highlighting their applications in studying disease physiopathology and drug development. In addition, advanced human iPSC-derived technologies, including organoids and organ-on-a-chip systems, are discussed highlighting their potential, current limitations, and future perspectives.

Keywords:  Amyotrophic Lateral Sclerosis; astrocytes; in vitro models; induced pluripotent stem cells; motor neurons

DOI:  https://doi.org/10.3390/cells15191798
Cells. 2026 Sep 29. pii: 1768. [Epub ahead of print]15(19):

Human iPSC-Derived Brain Cells, Organoids, and Organoids-on-Chips: Advancing Neurological Disease Modeling to Improve Clinical Outcome.

Gabriel Burdman, Marco Hanna, Adriana Yndart Arias, Arti Vashist, Madepalli K Lakshmana.

  Neurological disorders are the leading cause of overall disease and disability worldwide, affecting more than 3.4 billion people globally and over 180 million Americans. Yet there are no curative treatments available for any of the cardinal neurological diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) and Huntington's disease (HD). Many compounds that demonstrate excellent activity in preclinical models fail in clinical trials. The most compelling reason for this failure is attributed to inherent limitations of rodent models that fail to replicate complex human biology. The transformation of patient-derived somatic cells into induced pluripotent stem cells (iPSCs) that can become functional human neurons is an emerging technology that is expected to revolutionize medical treatments and personal medicine. Here, we review the available evidence for the efficacy of iPSC-derived neurons, organoids, assembloids and organ-on-chip in models of AD, PD, ALS-FTD and HD. We focus on how these human-relevant iPSC-derived brain cells are crucial for understanding neurological disease pathogenesis and accelerating drug discovery. We also discuss the current limitations of this technology and how alternative models such as induced neurons (iNs) are generated by directly reprogramming fibroblasts that preserve age-associated epigenetic signatures and may serve as better models for neurological disorders.

Keywords:  Alzheimer’s disease; CRISPR; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; assembloids; human induced pluripotent stem cells; organoids; translational validation

DOI:  https://doi.org/10.3390/cells15191768
J Vis Exp. 2026 Oct 13.

Isolated Axoplasm from Squid and Pathogenic Mechanisms in Amyotrophic Lateral Sclerosis.

Amanda Onoichenco, Sarah L Morris, Sarah Aloe, Kaitlynn McCay, Yuyu Song, Scott T Brady.

The squid giant axon is an experimental model that has been instrumental in providing answers to many fundamental questions in cell biology, including the discovery of the motor protein kinesin and probing molecular mechanisms of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). The giant axon offers scale and ease of access that is not possible in mammalian models. The power of this model stems from the fact that one can introduce reagents and proteins that would not cross a plasma membrane at defined concentrations in a buffer environment that is closely modeled on normal components of the axoplasm. By leveraging the unique biology of the squid axon, early studies were able to define the channels and ion specificities of the action potential. Subsequent studies using video-enhanced contrast- differential Interference contrast microscopy (VEC-DIC) and the isolated axoplasm led to the identification of kinesins, a class of motor proteins responsible for intracellular vesicle trafficking toward the plus end of microtubules. This combination of isolated axoplasm and advanced imaging continues to provide insights into pathogenic mechanisms for adult-onset neurodegeneration, including ALS, and regulation of fast axonal transport, a process disrupted in motor neuron disease. Here, procedures for dissecting the giant axon, isolating axoplasm, and perfusing defined amounts of proteins and/or reagents into the axoplasm are detailed, as well as methods for visualizing and interactively analyzing vesicle traffic in real time. This model represents a singular avenue to understand the critical function of neurons, shedding light on the mechanisms driving ALS pathology and other neurodegenerative diseases. This system also offers a tractable platform for drug testing, where candidate therapeutic compounds can be introduced directly into the axoplasm, and their effects on vesicle trafficking can be assessed in real time, providing a rapid and physiologically relevant means of identifying potential ALS therapeutic targets.

DOI: https://doi.org/10.3791/72560
bioRxiv. 2026 Oct 01. pii: 2026.09.23.753732. [Epub ahead of print]

Early life social isolation primes flies for more rapid TDP-43 dependent neurodegeneration later in life.

S MurthyGowda, K Huyghue, B Castillo, F Gugala, W Li, J Dubnau.

A key pathophysiological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is loss of nuclear localization and abnormal cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43). Upstream factors that trigger the onset and progression of such neurodegenerative diseases are largely unknown. Aging and environmental factors contribute as potential risk factors. But epidemiological evidence suggests psychological stressors such as social isolation and loneliness are also associated with increased risks of neurodegenerative disease [1-8]. We examined the impacts of social isolation on TDP-43 related neurodegeneration. To investigate the potential for causative impact on neurodegeneration, we compared the effects of social isolation versus social enrichment in Drosophila . We utilized an established social isolation paradigm in which flies were either housed alone or in groups as young adults. We found that early-life social isolation acts as a primer to exacerbate the rate of neurodegeneration in response to subsequent induction of pathological levels of TDP-43. Social isolation stress drives more rapid activation of mdg4, an endogenous retrovirus that functionally mediates TDP-43 effects and more aggressive propagation of TDP-43 protein pathology from surface glial cells to nearby neurons. Shortened life span also ensues. We demonstrate that providing isolated flies with visual, olfactory and tactile social cues from conspecifics living behind a divider was insufficient to alleviate these effects of social isolation on neurodegeneration. Our findings have implications for the association between psychological stressors such as loneliness and risk of neurodegenerative diseases in humans and provide a platform to investigate mechanistic underpinnings in animal models.

DOI: https://doi.org/10.64898/2026.09.23.753732
Phys Act Nutr. 2026 Sep;30(3): 97-113

Integrative ALS therapy: gene targeted therapy by base editing and potential exercise rehabilitation as synergistic strategies for functional recovery.

Kwangjun Lee, Taejin Kwak, Wonil Park.

   PURPOSE: A key pathological hallmark of amyotrophic lateral sclerosis (ALS) is transactive response DNA-binding protein 43 (TDP-43, encoded by TARDBP) proteinopathy. Mutations in TARDBP and cellular stress can drive nuclear clearance and cytoplasmic aggregation of TDP-43. TDP-43 is an essential nuclear RNA-binding protein that regulates RNA metabolism, and cytoplasmic TDP-43 aggregation leads to aberrant splicing of essential neuronal transcripts including stathmin-2 (STMN2) and unc-13 homolog A (UNC13A). Dysregulated RNA splicing causes cryptic exon (CE) inclusion in STMN2 and UNC13A mRNA, resulting in non-functional proteins and disruption of axonal regeneration and synaptic integrity. Splice-switching antisense oligonucleotides and gene-editing platforms can correct STMN2 and UNC13A mis-splicing defects. However, restoring STMN2 and UNC13A expression alone is not sufficient to regenerate neuromuscular junctions or reverse skeletal muscle atrophy, both of which are crucial for functional recovery in patients with ALS.
METHODS: We reviewed gene-targeted treatment strategies and rehabilitative mechanisms that inhibit ALS progression and reverse neuromuscular degeneration by analyzing databases, including Google Scholar, PubMed, and ScienceDirect. We proposed a dual-modality therapeutic approach integrating base-editing-mediated gene therapy with exercise-based rehabilitation.
RESULTS: Antisense oligonucleotides and genome editing can restore transcript fidelity by preventing cryptic exons inclusion in STMN2 and UNC13A, thereby stabilizing neuronal function. Gene-targeted therapies halt ALS progression; however, these treatments alone are insufficient to reverse neuromuscular degeneration or achieve functional recovery needed for patients with ALS to return to daily life.
CONCLUSION: Integrated rehabilitation is a crucial step in gene-targeted therapy for ALS. This strategy halts disease progression and restores neuromuscular function, thereby improving the lifespan and quality of life of patients with ALS.

Keywords:  TDP- 43 proteinopathy; amyotrophic lateral sclerosis (ALS); antisense oligonucleotides (ASOs); exercise rehabilitation; genome editing

DOI:  https://doi.org/10.20463/pan.2026.0045
Metab Brain Dis. 2026 Oct 14. pii: 235. [Epub ahead of print]41(1):

The small giant actor in the pathogenesis of neurodegenerative diseases: Microtubules.

Aslı Aksoy Gündoğdu, Neslihan Gücüyener Özkan, Demet Özbabalık Adapınar.

  Neurodegenerative diseases are a clinically and pathologically diverse group of disorders characterized by progressive neuronal dysfunction, synaptic impairment, and neuronal loss. Although research has traditionally focused on disease-associated protein misfolding and aggregation, increasing evidence implicates abnormalities of cytoskeletal organization and intracellular transport in several neurodegenerative conditions. Microtubules contribute to neuronal polarity, axonal and dendritic transport, organelle distribution, and synaptic maintenance. These functions are regulated in part by tubulin isotypes, post-translational modifications collectively described as the tubulin code, microtubule-associated proteins, and molecular motors. This narrative review examines evidence linking alterations in these processes with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. We summarize proposed interactions among microtubule instability, impaired axonal transport, mitochondrial dysfunction, and disease-associated proteins, including tau, α-synuclein, mutant huntingtin, TDP-43, and prion protein. Evidence connecting tau pathology with microtubule dysfunction is comparatively well established in Alzheimer's disease and MAPT-related tauopathies, whereas findings in other disorders are more heterogeneous and are frequently derived from cellular or animal models. We also discuss emerging experimental approaches, candidate biomarkers, and investigational microtubule-directed treatments. However, no tubulin-specific biomarker or microtubule-targeted disease-modifying treatment discussed in this review has yet been clinically validated. Overall, microtubule dysfunction may represent one component of broader, disease-specific pathological networks rather than a universal primary cause of neurodegeneration. Further longitudinal and clinical studies are needed to determine whether microtubule-related alterations act as causes, consequences, or modifiers of disease progression.

Keywords:  Axonal transport; Microtubule dynamics; Neurodegeneration; Tauopathy; Tubulin code; α-synuclein

DOI:  https://doi.org/10.1007/s11011-026-02001-9
Handb Clin Neurol. 2026 ;pii: B978-0-443-19043-8.00014-1. [Epub ahead of print]219 381-397

DNA methylation in motor neuron biology and epigeneticopathy in amyotrophic lateral sclerosis.

Lee J Martin.

  Amyotrophic lateral sclerosis (ALS), the 3rd most frequent neurodegenerative disease, is fatal. Skeletal muscles, neuromuscular junctions, and motor neurons in the cerebral cortex, brainstem, and spinal cord that control swallowing, breathing, and movement degenerate, causing paralysis, respiratory arrest, and death. Clinically meaningful disease mechanisms are unknown, and no effective therapies are available. ALS is a polygenic heterogeneous disease seen in 5%-10% of patients as inherited, but most patients have no inheritance pattern. ALS appears to manifest as a complex interplay between many genes in multiple tissues, individual lifestyle, the environment, and metabolism. Monozygotic twin and triplet studies of ALS suggest that epigenetic mechanisms could be involved in the pathogenesis because discordance is seen. Epigenetic anomalies involving DNA and RNA methylation occur in human ALS. Cell and animal models show that motor neuron development and degeneration can be regulated by DNA methylation. This chapter summarizes the DNA and RNA epigenetic anomalies that are prominent in human ALS and models of ALS, concluding with the suggestion that they are promising therapeutic targets with small molecules.

Keywords:  6-Methyladenosine; Cytosine methylation; DNMT3A; Motor neuron; RNA demethylase

DOI:  https://doi.org/10.1016/B978-0-443-19043-8.00014-1
bioRxiv. 2026 Oct 02. pii: 2026.09.28.755069. [Epub ahead of print]

ALS/FTD-linked TDP-43 alterations prevent HSV-1 infection by disrupting cell-adhesion pathways.

Stephanie Jackvony Infurna, Laraib Ijaz, Evelyn J Hardin, Abulimiti Aikedan, Constance Zhou, Tejabhiram Yadavalli, Minwoo Wendy Jang, Matthew Mahoney, Li Gan, Deepak Shukla, Adam L Orr, Anna G Orr.

TAR DNA-binding protein-43 (TDP-43) alterations are a key hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative disorders. Increasing evidence links these conditions to viral infections, but it is not known if and how viral pathogens may be affected by disease-associated TDP-43. We found that ALS/FTD-linked forms of human TDP-43 prevent infection by herpes simplex virus type-1 (HSV-1), a common neurotropic virus. This cell-autonomous protective effect was conserved across different TDP-43 mutations, sporadic ALS, and C9ORF72 -ALS, in neural and non-neural cell types, and in patient-derived cells and animal models. In addition to restricting infection, TDP-43 mutation prevented inflammatory and cell stress-related responses to HSV-1 exposure. TDP-43 knockdown but not overexpression was sufficient to protect cells from HSV-1 infection, implicating a loss-of-function mechanism. Neurons with TDP-43 mutation had disruptions in adhesion-related pathways and, accordingly, had reduced early-stage viral binding and entry. Further analyses revealed alternative RNA splicing and impairment of focal adhesion kinase (FAK/PTK2), a key mediator of cell-adhesion pathways. Inhibition of FAK was sufficient to decrease HSV-1 infection, and genetic enhancement of functional but not inactive FAK promoted infectivity in cells with TDP-43 mutation. Together, these data indicate that TDP-43 affects virus-host interactions by influencing adhesion pathways required for viral infection.

DOI: https://doi.org/10.64898/2026.09.28.755069
Cell Rep. 2026 Oct 15. pii: S2211-1247(26)01131-9. [Epub ahead of print]45(10): 118053

Ataxin-2 downregulation rewires neuronal and astrocytic metabolism to protect against TDP-43 toxicity.

Denise Gastaldo, Stephen Vito, Holly H Black, Oded Foreman, Zhichang Yang, Victoria Pham, Ying Zhu, Meena Choi, Ana Jovičić.

  Ataxin-2 (ATXN2) is a genetic modifier of TDP-43 toxicity and a promising therapeutic target in amyotrophic lateral sclerosis (ALS). However, the mechanisms underlying its neuroprotective effects remain poorly understood. Using global proteomic profiling in yeast and mouse TDP-43 models, we establish that pbp1/ataxin-2 (pbp1 is the yeast ataxin-2 ortholog) reduction confers neuroprotection by activating orthogonal stress-adaptive pathways in neurons and glia, rather than simply reversing TDP-43-induced damage. In neurons, ataxin-2 downregulation activates glycolysis and reductive glutamine carboxylation driven by IDH1, restoring ATP production independently of impaired mitochondria. In astrocytes, it upregulates cholesterol biosynthesis via HMGCS1, enhancing trophic support to neurons. Full neuroprotection requires both mechanisms: neuronal survival is only completely rescued when ataxin-2 is reduced in neuron-astrocyte co-cultures. Importantly, ataxin-2 downregulation protects against both TDP-43 gain- and loss-of-function toxicity, broadening its therapeutic relevance. Collectively, these findings establish ataxin-2 as a regulator of stress-adaptive metabolic resilience.

Keywords:  ALS; ALS therapy; CP: metabolism; CP: neuroscience; TDP-43; ataxin-2; cholesterol; glutamine reductive carboxylation; glycolysis; mechanisms of neuroprotection; neurodegeneration; neuronal metabolism; neuroprotection

DOI:  https://doi.org/10.1016/j.celrep.2026.118053
J Clin Invest. 2026 Oct 15. pii: e209602. [Epub ahead of print]136(20):

Modeling human neurodegeneration with iPSCs: opportunities, limitations, and the challenge of aging.

Shijie Wang, Lisa Elia, Weiyi Liu, Steven Finkbeiner.

Most neurodegenerative diseases reflect patient-specific combinations of polygenic risk variants interacting with aging and environmental factors, rather than a single causative mutation. Phase III clinical trial failure rates for neurodegenerative indications exceed 95%, reflecting in part the limitations of existing preclinical systems to fully model the human genetic context of disease. Patient-derived induced pluripotent stem cells (iPSCs) have the potential to address this shortcoming by faithfully recapitulating human cell biology and preserving each patient's complete genetic architecture. This Review examines iPSC-based models of neurodegeneration across three themes. First, we discuss mechanisms revealed by these models, from convergent pathways uncovered by familial mutations to early evidence that sporadic disease biology is accessible at sufficient cohort scale. Second, we evaluate culture systems from 2-dimensional monocultures to organoids, examining how increasing complexity expands addressable biological questions while introducing trade-offs. Third, we address the aging problem: reprogramming erases epigenetic signatures of donor aging, removing the cellular context in which late-onset sporadic neurodegeneration emerges. We discuss strategies approximating aging in iPSC-derived neurons and highlight direct conversion strategies that preserve native epigenetic age, enabling access to age-dependent phenotypes. We propose a framework matching model systems to biological questions, improving mechanistic understanding and therapeutic development.

DOI: https://doi.org/10.1172/JCI209602
Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2627551123

Membrane contact activation of Piezo2 drives lysosome-mitochondrion Ca2+ transfer and signaling in Trypanosoma cruzi.

Guozhong Huang, Roberto Docampo.

  Calcium ion (Ca2+) transfer from other organelles is central to mitochondrial metabolism and cell survival, yet how mechanical forces regulate interorganelle communication remains unclear. Here we report a lysosome-to-mitochondrion pathway in Trypanosoma cruzi, the etiologic agent of Chagas disease, mediated by the mechano/osmosensitive channel TcPiezo2. Using ultrastructural, biochemical, and live-cell superresolution imaging, we define lysosome-mitochondrion contact sites (LMCs) that enable direct Ca2+ transfer. TcPiezo2 triggers Ca2+ release, which generates perilysosomal nanodomains that drives mitochondrial Ca2+ uptake via the voltage-dependent anion channel and the mitochondrial Ca2+ uniporter complex. Disruption of TcPiezo2-dependent Ca2+ transfer impairs mitochondrial metabolism, perturbs redox homeostasis, induces autophagy, and eventually leads to parasite death. These findings establish LMCs as a signaling platform that directly regulates interorganelle Ca2+ transfer and mitochondrial bioenergetics.

Keywords:  Piezo channel; calcium; lysosomes; membrane contact sites; mitochondria

DOI:  https://doi.org/10.1073/pnas.2627551123
Methods Mol Biol. 2026 ;3057 35-53

Engineering Functional Skeletal Muscle Tissues from Human Induced Pluripotent Stem Cells.

Amber Detwiler, Alastair Khodabukus, Nenad Bursać.

  In vitro cell culture models of human skeletal muscle offer a valuable platform for studies of pathology and discovery of new therapeutics. However, traditional two-dimensional cell culture models suffer from limited durability and challenges with assessment of skeletal muscle contractile function. Furthermore, finite proliferation potential and scarce availability of patient-derived primary myoblasts limit experimental throughput when using these cells. Here, we describe a method for using human induced pluripotent stem cells (hiPSCs) to generate functional three-dimensional skeletal muscle tissues. Briefly, transient overexpression of Pax7 in hiPSC-derived paraxial mesoderm cells permits efficient formation of myogenic progenitor cells (iMPCs), which are then combined with hydrogel matrix to form cylindrically shaped skeletal muscle (iSKM) "myobundles." After 2 weeks of differentiation, iSKM myobundles contain aligned and densely packed multinucleated myotubes that, in response to electrical stimulation, exhibit robust calcium transients and positive force-frequency and force-length relationships. The methods detailed here have been successfully utilized to model and study limb-girdle muscular dystrophy type R2/2B and can be applied for studies of skeletal muscle regeneration and testing of candidate gene and cell therapies for disease. Collectively, iSKM myobundle engineering is a powerful in vitro methodology expected to significantly advance human skeletal muscle research and therapy.

Keywords:  Disease modeling; Human induced pluripotent stem cells; Hydrogel; Myopathy; Skeletal muscle; Tissue engineering

DOI:  https://doi.org/10.1007/978-1-0716-5396-8_4
Biochem Pharmacol. 2026 Oct 13. pii: S0006-2952(26)00887-7. [Epub ahead of print] 118545

Conformational allocation of mitofusin 2 in neuronal mitochondrial dynamics: Mechanisms and therapeutic targeting.

Zhi-Yuan Zhang, Bo-Quan Qin, Shi-Zhou Wu, Hui Zhang.

  Neurons must sustain functional mitochondria far from the cell body. Mitofusin 2 (MFN2), a dynamin-like large guanosine triphosphatase (GTPase), coordinates outer mitochondrial membrane remodeling with axonal transport, bioenergetic support, inter-organelle communication, and stress-responsive quality control. Studying these activities separately obscures how disruption of one protein produces diverse neuronal phenotypes. We propose a testable conformational-allocation framework in which molecular state distributions and transition kinetics bias MFN2 participation across cellular outputs. Integrating structural and functional evidence, we distinguish experimentally resolved mechanisms from working models. Variants associated with Charcot-Marie-Tooth disease type 2A (CMT2A) are compared by the molecular step or functional output affected. Fusion loss alone does not capture this mechanistic diversity. Structure-guided docking supports local compatibility at a shallow, conformationally conditional C-terminal surface, without establishing native accessibility, affinity, or therapeutic response. CMT2A provides the strongest context for intervention, combining causal genetics, direct mitofusin engagement studies, and multiscale rescue. Amyotrophic lateral sclerosis (ALS) provides secondary preclinical evidence, whereas Alzheimer's and Parkinson's diseases remain exploratory. The mitofusin pathway is chemically tractable, but paralog selectivity and state-dependent target engagement remain unresolved. A state- and variant-informed strategy may better match intervention to the affected output than indiscriminate enhancement of fusion.

Keywords:  Axonal transport; Charcot–Marie–Tooth disease type 2A; Conformational allocation; Mitochondrial dynamics; Mitofusin 2; Pharmacological modulation

DOI:  https://doi.org/10.1016/j.bcp.2026.118545
Cells. 2026 Sep 30. pii: 1781. [Epub ahead of print]15(19):

Disrupting Mitochondrial Homeostasis via TBC1D15 Protein.

Pengfei Qiang, Yan Li, Shuang Liang, Miaomiao Jiang, Shuoye Yang, Xiwei Zhang.

   BACKGROUND: Mitochondria-lysosome coupling and mitophagy are fundamental to mitochondrial homeostasis, yet the determinants governing this process remain incompletely defined. This study distinguished the regulatory modes of TBC1D15 and established its functional role as a downstream effector in mitochondria-linked autophagy.
METHODS: PC-12 and HeLa cells were treated with CCCP, gradient-concentrated AuNPs, and CQ, combined with siRNA-mediated PINK1 knockdown. Whole-cell, mitochondrial and lysosomal fractions were analyzed by immunoblotting.
RESULTS: Inter-organelle translocation of TBC1D15, rather than its total abundance, serves as the critical switch for mitochondria-lysosome homeostasis. CCCP induced a time-dependent biphasic change in TBC1D15 that persisted upon PINK1 knockdown, indicating regulation is not strictly PINK1-dependent. High-dose AuNPs trapped TBC1D15 on mitochondria and blocked lysosomal delivery via a PINK1-independent route. AuNPs exhibited biphasic concentration-dependent effects: low concentrations moderately upregulated TBC1D15, promoting adaptive organelle contacts, while millimolar concentrations caused pathological tethering. Subcellular fractionation and CQ intervention confirmed that defective lysosomal delivery underlies mitochondrial TBC1D15 accumulation upon AuNP challenge.
CONCLUSIONS: This work establishes two distinct regulatory axes converging on TBC1D15. High-dose AuNPs can serve as a specific pharmacological blocker of TBC1D15 trafficking, offering therapeutic avenues for disorders characterized by impaired mitophagy.

Keywords:  TBC1D15; lysosomes; mitochondria; mitochondrial homeostasis

DOI:  https://doi.org/10.3390/cells15191781
Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2612539123

Double periodicity of the AnkyrinG-associated complex in the axon initial segment.

Gülberk Bayraktar, Josephine K Dannersø, Sean D S Hansen, Lisbeth Schmidt Laursen, U Valentin Nägerl, Poul Nissen.

  The axon initial segment (AIS), situated within the first 20 to 60 µm of the axon, is essential for action potential generation and maintenance of axonal identity [M. N. Rasband, Nat. Rev. Neurosci. 11, 552-562 (2010)]. Its structure relies on the beta (β)-IV-spectrin/AnkyrinG (AnkG) scaffold arranged periodically underneath the plasma membrane, harboring diverse membrane proteins [K. Xu, G. Zhong, X. Zhuang, Science 339, 452-456 (2013); K. L. Hedstrom, Y. Ogawa, M. N. Rasband, J. Cell Biol. 183, 635-640 (2008)]. Although a ~190-nm cytoskeletal periodic organization is well established, the precise stoichiometry and spatial arrangement of AIS proteins within the ~190-nm spatial period remain rudimentary, mostly for lack of sufficient spatial resolution and labeling efficiency. Here, using expansion microscopy and cryoelectron tomography, which overcome these technical limitations, we present data on the organization of the AnkG-associated complex within the ~190-nm spatial period. We demonstrate that exactly two AnkG molecules are situated within each period and with their C termini separated by ~80 nm. By contrast, the AnkG-associated cell-adhesion protein neurofascin-186 appears in clusters of varying sizes that are consistent with the periodic organization of AnkG pairs, yet suggesting a more complex molecular arrangement between the two molecules. Altogether, our approach provides insights into AIS molecular organization and protein stoichiometry.

Keywords:  ankyrin-G; axon initial segment; neurofascin-186; ultrastructure; voltage-gated potassium channel

DOI:  https://doi.org/10.1073/pnas.2612539123
Methods Mol Biol. 2026 ;3057 55-67

Bulk Differentiation of Human Induced Pluripotent Stem Cells into Contractile Skeletal Muscles.

Yu-Shen Cheng, Farah Ulfat Jamee, Muhammad Irfanur Rashid, Hidetoshi Sakurai, Kazunori Shimizu, Yohei Okada.

  Effective treatments for various muscular disorders and a clear understanding of their disease pathology remain lacking owing to the limitations of traditional animal models and two-dimensional (2D) cell cultures. Human induced pluripotent stem cells (hiPSCs) offer promising platforms for disease modeling and regenerative medicine. However, existing protocols for skeletal muscle differentiation are often labor-intensive and yield inconsistent results. Here, we utilized a piggyBac transposon-based system to generate bulk MYOD1-hiPSCs, eliminating the need for clonal selection and enabling rapid, efficient, and reproducible skeletal muscle differentiation. Furthermore, we established a protocol for generating functional three-dimensional (3D) skeletal muscle tissues that exert contractile force in response to electrical stimulation, highlighting their physiological relevance. This system provides a simple and valuable tool for disease modeling, drug screening, and the study of sporadic muscle disorders using patient-derived hiPSCs.

Keywords:  3D culture; Bulk culture; Contraction; Disease modeling; MYOD1-hiPSC; Skeletal muscle differentiation

DOI:  https://doi.org/10.1007/978-1-0716-5396-8_5
J Pharmacol Exp Ther. 2026 Sep 23. pii: S0022-3565(26)01235-8. [Epub ahead of print]393(11): 105035

Leucine-rich repeat kinase 2 is involved in the microtubule-mediated regulation of intraocular pressure.

Yuji Takahashi, Masaki Ito, Reijiro Arakawa.

  Leucine-rich repeat kinase 2 (LRRK2) is known as the most common gene responsible for familial Parkinson disease (PD). This protein plays a key role in the neurodegenerative pathways associated with PD. LRRK2 also plays critical roles in actin dynamics and microtubule cytoskeletal assembly in the cells. In addition to PD, actin and microtubule cytoskeletons are associated with the onset and development of glaucoma by regulating the intraocular pressure (IOP) in humans and animals. However, the role of LRRK2 in regulating IOP remains unclear. Hence, this study investigated the contribution of LRRK2 to cytoskeleton-mediated regulation of IOP. LRRK2 was detected in primary human trabecular meshwork cells by immunofluorescence and western blotting analysis. Inhibition of the function and the expression of LRRK2 by LRRK2 inhibitors and LRRK2 siRNA, induced a significant reduction of TEER in these cells. TEER reduction by an LRRK2 inhibitor was attenuated by paclitaxel, a-tubulin polymerization inducer, but not by jasplakinolide, an actin polymerization inducer, suggesting that inhibition of LRRK2 induced depolymerization of microtubules, resulting in decreased TEER. Finally, LRRK2 gene knockout and LRRK2 inhibition led to a significant reduction of IOP in C57BL6J mice and Japanese white rabbits, respectively. These results suggested that LRRK2 is associated with catalysis of a-tubulin in trabecular meshwork cells and regulates IOP in mice and rabbits. Hence, there is a possibility that an LRRK2 inhibitor contributes to glaucoma therapeutics. Further evaluation to clarify the role of LRRK2 in IOP regulation is needed. SIGNIFICANCE STATEMENT: In this study, a significant contribution of LRRK2 to the regulation of intraocular pressure (IOP) was shown. Inhibition of LRRK2 results in a decrease in TEER of the trabecular meshwork cells, associated with the depolymerization of microtubules. Furthermore, both LRRK2 knockout and administration of the LRRK2 inhibitor induced a significant decrease in the IOP in animals. These results clearly indicate the role of LRRK2 in the regulation of IOP and the possibility of a novel therapeutic approach to glaucoma.

Keywords:  Cytoskeleton; Intraocular pressure; LRRK2; Microtubule depolymerization

DOI:  https://doi.org/10.1016/j.jpet.2026.105035
J Huntingtons Dis. 2026 Oct 16. 18796397261497434

iPSC neurodegenerative disease initiative isogenic CAG repeat iPSC line for Huntington's disease.

Lisa Salazar, Mara S Burns, Jennifer T Stocksdale, Keona Q Wang, Gloria Cao, Ricardo Miramontes, Nicolette R McClure, Leanne Ho, Amber Rose Keith, Margaret Sutherland, Mark R Cookson, Michael Ward, William C Skarnes, Leslie M Thompson.

  Purpose of ResearchThe generation of iPSC lines expressing 21, 56 and 79 glutamine repeats within the HTT protein and homozygous KO of HTT in the KOLF2.1J background as an additional disease series within the iPSC Neurodegenerative Disease Initiative (iNDI) collection.Major FindingsAll iPSCs, even those expressing long repeats of 79Q or HTT KO, were capable of differentiating to striatal and cortical neurons, astrocytes and microglia using established protocols. General quality control stains and morphological analyses are described for each differentiation. A selected set of assays were carried out on differentiated cells; expanded repeat expressing astrocytes showed altered expression of astrocyte protein markers and morphological characteristics, and striatal neurons showed altered DARPP-32/CTIP2 colocalization. mRNAseq carried out for striatal neurons showed high similarities in gene expression changes between 79Q and KO lines compared to the unexpanded repeat.ConclusionsThe KOLF2.1J isogenic CAG repeat series serves as a community resource to study HD mechanisms with the potential for direct comparison across other neurodegenerative diseases through the iNDI collection.

Keywords:  CRISPR; Huntingtin; astrocyte; differentiation; iNDI; iPSC; microglia; neuron

DOI:  https://doi.org/10.1177/18796397261497434
Dev Neurosci. 2026 Oct 15. 1

Late endosome trafficking is slower in regenerated dendrites.

Yuting Liu, Vinicius N Duarte, Katherine L Thompson-Peer.

Organelle trafficking is essential for neuronal function and homeostasis, particularly in dendrites where transport is required to maintain complex arbors. Following dendritic injury, extensive cellular reorganization occurs during regeneration, yet how this remodeling affects organelle transport dynamics remains poorly understood. To assess the consequences of regeneration on dendritic trafficking, we examined Rab7-labeled late endosome (LE) movement in class IV dendritic arborization neurons of Drosophila after dendrite injury. Using quantitative live imaging analysis, we found that retrograde LE trafficking speed is significantly reduced in regenerated dendrites compared to uninjured controls. However, anterograde LE trafficking speed, the directional bias of LE movement, the proportion of motile versus stationary organelles, LE number, and run length were not significantly different between uninjured versus regenerated neurons at either time point examined. These findings demonstrate that dendritic regeneration selectively impairs retrograde transport kinetics while preserving anterograde transport and directional control mechanisms. Regenerated dendrites are thinner than uninjured controls at early stages of regrowth but recover to normal caliber by later stages, yet retrograde transport deficits persist, suggesting caliber-independent regulation of retrograde transport speed. Our results suggest that altered organelle trafficking dynamics may represent a fundamental consequence of neuronal injury responses, with potential implications for understanding transport defects in regeneration after injury or disease involving dendritic damage.

DOI: https://doi.org/10.1159/dne/aclag007
Methods Mol Biol. 2026 ;3057 145-158

Extracellular Vesicle Isolation and Purification from Skeletal Muscle Cells.

Dongnan Yan, Emily Haughton, Ruhani Makkar, Matthew J A Wood, Dhanu Gupta.

  Extracellular vesicles (EVs) have emerged as critical mediators of intercellular communication and hold considerable promise as biomarkers and therapeutic vectors. In skeletal muscle, EVs transport proteins, RNA, and other bioactive molecules, such as myokines, making them valuable indicators of muscle physiology and pathology. This method paper presents a detailed protocol for the isolation, purification, and characterization of EVs derived from human myoblasts. Our optimized workflow ensures high yield and sample quality, enabling comprehensive downstream molecular analysis. Additionally, we describe advanced techniques for assessing EV physical characteristics, concentration, and cargo content, providing an essential toolkit for investigating skeletal muscle EV biology and potential role in disease diagnostics. This protocol facilitates the efficient exploration of skeletal muscle-derived EVs and their implications in muscle function and pathology.

Keywords:  EV characterization; EV isolation; EV purification; Extracellular vesicles; Skeletal muscle; Ultracentrifugation

DOI:  https://doi.org/10.1007/978-1-0716-5396-8_12
Acta Neuropathol. 2026 Oct 13. pii: 54. [Epub ahead of print]152(1):

CHCHD2 mitigates age-associated proteostatic collapse by maintaining homeostasis of the mitochondria-lysosome axis.

Teresa R Kee, Brianna M Masters, Khoi D Tran, Hanna Jeon, Ma Long, Grace Xu, Sophia A Khan, Edwin Vázquez-Rosa, Preethy S Sridharan, Yeojung Koh, Hisashi Fujioka, Dale Chaput, Xinming Wang, Xingyu Zhao, Andrew A Pieper, David E Kang, Jung-A A Woo.

  Mutations in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), including the Parkinson's disease (PD)-linked CHCHD2T61I mutation, are associated with Lewy body disorders (LBDs) by unknown mechanisms. Here, we demonstrate that CHCHD2T61I exacerbates age-related brain pathologies, including axonal degeneration and cognitive deficits, by disrupting the mitochondria-lysosome axis. Specifically, CHCHD2T61I binds and reduces cathepsin B (CTSB) and cathepsin L (CTSL) levels, inducing lysosomal membrane permeability and impairing α-synuclein fibril clearance. We also demonstrate that human CHCHD2 declines in the brain with age, while expression of wild-type CHCHD2 safeguards against age-related neuroinflammation, dopaminergic neuron loss, insoluble protein aggregation, and structural deterioration of mitochondria and lysosomes. These findings, supported by observed reductions in CTSB and CHCHD2 in human LBD brains, establish CHCHD2 as a key regulator of neuronal resilience to aging and proteostatic collapse via the mitochondria-lysosome axis. Preventing age-associated CHCHD2 decline offers a therapeutic strategy to preserve brain health throughout aging.

Keywords:  Aging; CHCHD2; Lewy body disorders; Mitochondria-lysosome axis

DOI:  https://doi.org/10.1007/s00401-026-03093-4
bioRxiv. 2026 Oct 03. pii: 2026.01.16.700014. [Epub ahead of print]

Local ROS and inefficient autophagosome formation limit Optineurin-mediated mitophagy in neurons.

Jordan R Green, Anne E Ojo, Molly K Gooden, Lillian D Papell, Titilola D Kalejaiye, Chantell S Evans.

Mitophagy is a quality control mechanism that maintains neuronal health by removing damaged mitochondria. In neurons, mitophagy can be driven by Optineurin (OPTN), a selective autophagy receptor recruited in response to oxidative stress. However, mechanistic studies of mitophagy have relied mainly on non-neuronal cell lines and acute damage paradigms. It remains unknown whether these findings translate to neurons under physiological stress conditions. Here, we investigated the temporal dynamics of OPTN-dependent mitophagy under mild oxidative stress using live-cell imaging in primary rat hippocampal neurons. We found that autophagosomes failed to readily engulf OPTN-positive (OPTN+) mitochondria, revealing a previously unidentified rate-limiting step in neuronal OPTN-mediated mitophagy. Additionally, OPTN+ mitochondria colocalized with acidified lysosomes over timescales significantly longer than previously reported. These OPTN+ mitochondria displayed locally elevated reactive oxygen species (ROS). Scavenging mitochondrial ROS increased lysosomal colocalization with damaged mitochondria and accelerated mitophagy progression. Together, these findings indicate that redox signaling contributes to the slow timescale of OPTN-mediated mitophagy in neurons.

DOI: https://doi.org/10.64898/2026.01.16.700014
Pflugers Arch. 2026 Oct 14. pii: 93. [Epub ahead of print]478(11):

Revisiting the muscle spindle in ALS: Implications for spinal motor network dysfunction.

José Castro, Mamede de Carvalho, Michael Swash.

  Amyotrophic lateral sclerosis (ALS) is typically characterized by progressive degeneration of upper and lower motor neurons. However, the contribution of afferent sensory pathways to spinal motor network disorganization has received little attention. Converging human histological evidence from multiple independent laboratories demonstrates that fusimotor (gamma) motor neuron innervation of muscle spindles degenerates in ALS while sensory endings remain morphologically intact at the end organ, although the afferent neurons and ascending sensory pathways are also affected. This dissociation creates unmodulated proprioceptive input. Spindle-derived sensory signals reach spinal interneuron circuits without fusimotor gain-control adjustment, degrading spindles from forward sensory models encoding predicted kinematic states into crude stretch receptors. We propose that this gain-control failure, compounded by the loss of associated alpha-gamma coactivation and beta skeletofusimotor denervation, constitutes an upstream driver of the spinal inhibitory interneuron circuit dysfunction documented by recent electrophysiological studies in ALS. The resulting early disinhibition, followed by maladaptive excitation, mirrors cortical ALS pathophysiology. However, transgenic mouse ALS models show selective sparing of gamma motor neurons, unlike the human disease, constituting a critical translational limitation. We present a temporal model of human ALS, linking fusimotor denervation to progressive disruption of spinal inhibitory and excitatory circuits.

Keywords:  Amyotrophic lateral sclerosis; Fusimotor denervation; Gamma motor neuron; Muscle spindle; Proprioception; Spinal interneuron

DOI:  https://doi.org/10.1007/s00424-026-03224-6
Nat Commun. 2026 09 10. pii: 10711. [Epub ahead of print]17(1):

Mapping high resolution, multidimensional phase diagrams of near-physiological protein condensates.

Tanushree Agarwal, Tomas Sneideris, Fabian Svara, Klavs Jermakovs, Helena Coyle, Seema Qamar, Emanuel Kava, Rob Scrutton, Nicole Pleschka, Priyanka Peres, Gea Cereghetti, Ewa Andrzejewska, Alejandro Diaz-Barreiro, Gaby Palmer, Antonio J Costa-Filho, Georg Krainer, Tuomas Pj Knowles, Jonathon Nixon-Abell.

Biomolecular condensates are membraneless compartments, crucial for organising and regulating diverse cellular processes. Current approaches to study condensate biology either use simplified recombinant protein systems with limited physiological relevance, or complex live-cell models with restricted experimental control and scalability. Here, we present ExVivo PhaseScan, a droplet microfluidics platform that couples mammalian lysate-based reconstitution with scalable analysis to generate high-resolution phase diagrams of compositionally complex protein condensates. We apply this approach to study two multicomponent condensate systems, stress granules and nucleoli, and dissect the physicochemical interactions that influence their stability. We further developed a machine learning pipeline to analyse condensate morphology which we use to reveal how mutations in the amyotrophic lateral sclerosis (ALS)-linked protein Fused in Sarcoma (FUS) remodels condensate properties. We identify liquid-to-solid transitions of mutant FUS within stress granules and nucleoli, and show that these transitions can be reversed by RNA aptamer-based interventions. Together, these findings establish ExVivo PhaseScan as a versatile tool for dissecting the physicochemical and pathological regulation of condensates, with potential to inform therapeutic strategies for diseases driven by aberrant phase transitions.

DOI: https://doi.org/10.1038/s41467-026-77696-6
Cells. 2026 Sep 30. pii: 1789. [Epub ahead of print]15(19):

Mitofusin Activation Delays Aging in Caenorhabditis elegans.

Jochen Weigele, Lihong Zhang, Jiajia Li, Elisabeth Roider, Caroline E Walton, Gerald W Dorn.

  Age-linked tissue dysfunction is associated with mitochondrial degeneration manifested as organelle fragmentation and respiratory dysfunction. Efforts to mitigate downstream consequences of mitochondrial degeneration, as with ROS scavengers, have not translated to the human condition. We posit that intrinsic fusion-mediated mechanisms for mitochondrial protection modulate aspects of aging linked to mitochondrial abnormalities. In C. elegans roundworms mitochondrial fusion is mediated by the mitofusin ortholog Fuzzy Onion-1 (fzo-1). Here, the addition of a mitofusin inhibitor, MFI8, to cultures of age-synchronized C. elegans shortened worm lifespan in a concentration-dependent manner. Reciprocally, the mitofusin activators Chimera and 8015-P2 prolonged worm survival in a dose-dependent manner. The pro-survival effect of Chimera was absent in worms lacking its protein target, FZO-1, and at lower concentrations Chimera-amplified survival was further increased by absence of the mitochondrial fission protein that acts in opposition to fzo-1, DRP-1. The mitofusin activator 8015-P2, which is more potent than Chimera, exhibited greater anti-aging effects on lifespan and improved worm healthspan measured as forced swimming activity and resistance to thermal and oxidative stresses. These proof-of-concept worm studies identify aging phenotypes reciprocally related to fzo-1/mitofusin activation status. As 8015-P2 is under development for use in human neurodegenerative diseases, it might alleviate aging phenotypes evoked by mitochondrial degeneration in higher species.

Keywords:  healthspan; lifespan; mitochondrial fusion

DOI:  https://doi.org/10.3390/cells15191789
Sci Adv. 2026 Oct 16. 12(42): eaed8795

MFN2-associated astrocyte dysfunction contributes to neuronal hyperexcitability and depressive-like behaviors.

Feng-Xia Ma, Min Wang, Shuo-Yan Fang, Xiao-Xin Wang, Shen-Han Xu, Xin-Xin Zhao, Yu-Xiao Liu, Cong Wang, Chen Qiao, Qiu-Ling Wang, Lei Cao.

Astrocyte pathology is increasingly recognized as a key factor in the pathogenesis of major depressive disorder (MDD), where disrupted glutamate clearance and impaired neuron-glia interactions contribute to synaptic dysfunction. However, the molecular mechanisms leading to astrocyte loss remain largely undefined. Mitochondrial dysfunction is a hallmark of MDD, yet most studies have focused on neuronal mitochondria, leaving astrocytic mitochondrial dynamics insufficiently investigated. Here, we identify mitofusin-2 (MFN2)-associated astrocyte dysfunction in depression. SMART-seq profiling of hippocampal astrocytes from chronic social defeat stress (CSDS) mice revealed Mfn2 up-regulation, accompanied by excessive mitochondrial fusion, impaired mitophagy, and astrocyte loss. Elevated MFN2 expression was detected in plasma, postmortem brain tissue, and iPSC-derived astrocytes from patients with MDD. Astrocyte-specific knockdown of Mfn2 restored mitochondrial morphology and mitophagy, thereby preserving astrocyte viability and alleviating depressive-like behaviors. Using mass spectrometry-based label-free proteomics, in vivo calcium imaging, and functional assays, we demonstrated that β-arrestin2 deficiency reduced STAT1 stability, releasing its transcriptional repression on Mfn2. Normalization of MFN2 expression through astrocytic Mfn2 knockdown or Stat1 overexpression reduced extracellular glutamate accumulation and prevented neuronal hyperexcitability in CSDS mice. Collectively, our findings define astrocytic MFN2-associated astrocyte dysfunction as a central pathological event in depressive behaviors, with the β-arrestin2-STAT1 pathway acting as an upstream regulatory mechanism. This work reveals an astrocytic pathway in depression and highlights a potential therapeutic target that directly addresses astrocyte pathology, beyond the neuron-centered focus of current antidepressant treatments.

DOI: https://doi.org/10.1126/sciadv.aed8795
Curr Neurovasc Res. 2026 Oct 07.

Role of Miro1 in Mitochondrial Dysfunction and Neurodegeneration in Huntington's Disease.

Mustak Ahamed, Khadga Raj Aran.

   INTRODUCTION: Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder that is caused by expansion of Cytosine-Adenine-Guanine (CAG) repeats in the Huntingtin (HTT) gene and leads to progressive motor, cognitive, and psychiatric dysfunction. Mitochondrial dysfunction is a major pathological feature of HD. Mitochondrial Rho GTPase 1 (Miro1) controls mitochondrial trafficking, calcium homeostasis, mitophagy, and neuronal signaling, and its dysregulation may contribute significantly to the progression of HD.
METHODS: The literature search to identify relevant studies on Miro1 biology, mitochondrial dysfunction, mitophagy, neuroinflammation, and emerging therapeutic strategies in HD followed a narrative review of the PubMed, Scopus, ScienceDirect, and Google Scholar databases. Original research articles, review articles, and preclinical studies published in English were screened for relevance, and the retrieved evidence was critically synthesized to provide an updated overview of Miro1's role in HD pathogenesis and its therapeutic potential.
RESULTS: Mutant Huntingtin (mHTT) perturbs Miro1-dependent mitochondrial transport, which leads to mitochondrial mislocalization, defective mitophagy, oxidative stress, and synaptic dysfunction. Miro1 dysregulation also facilitates neuroinflammatory signaling and neuronal vulnerability. Advances in AI have led to improved early diagnosis of HD through neuroimaging and digital biomarkers. Emerging therapies targeting Miro1, including gene therapy, nanocarriers, and pharmacological modulators, show promising neuroprotective potential in preclinical models.
DISCUSSION AND CONCLUSION: Miro1 is a potentially important molecular link between mitochondrial dysfunction and neurodegeneration in HD. Targeting Miro1-mediated pathways may restore mitochondrial homeostasis and may be a promising therapeutic strategy for disease modification.

Keywords:  Miro1; huntington’s disease; mitochondrial transport; mitophagy; neuroinflammation; synaptic plasticity

DOI:  https://doi.org/10.2174/0115672026501524261001101908