ArticleActa neuropathologica2021
Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis.
Article in Acta neuropathologica, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers.
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Who cites it
90 citing papers in PubMed, 135 citations in OpenAlex.
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- Trial
- Astrocytes regulate axonal mitochondrial transport deficits in C9ORF72 amyotrophic lateral sclerosis motor neurons.Nature neuroscience · 2026Article
- PolyQ-expanded ataxin-3 is associated with mitochondrial alterations in Machado-Joseph disease.Disease models & mechanisms · 2026Article
- Review
- ALS mutations do not alter perineuronal net formation in human stem cell-derived motor neurons.Communications biology · 2026Article
- Engineered GM1 Intersects Between Mitochondrial and Synaptic Pathways to Ameliorate ALS Pathology.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Transcriptomic and pathological analysis of the hnRNP network reveals glial involvement in frontotemporal lobar degeneration pathological subtypes.Brain communications · 2026Article
- C9orf72-ALS mutation drives basal mitophagy impairments in iNeurons.Frontiers in cellular neuroscience · 2026Article
- Axonal transport impairment as an upstream mechanism in amyotrophic lateral sclerosis pathogenesis.Frontiers in neuroscience · 2026Article
- Investigation of mitochondrial phenotypes in motor neurons derived by direct conversion of fibroblasts from familial ALS subjects.Cell death & disease · 2025Article
- Syntaphilin loss enhances mitochondrial axonal transport and neuromuscular junction formation in a human stem cell derived neuromuscular assembloid model.Molecular medicine (Cambridge, Mass.) · 2025Article
- Review
- C9orf72 hexanucleotide repeat expansions impair microglial response in ALS.Nature neuroscience · 2025Article
- Transcriptional modulation unique to vulnerable motor neurons predicts ALS across species and SOD1 mutations.Genome research · 2025Article
- TDP-43 pathology is associated with divergent protein profiles in ALS brain and spinal cord.Acta neuropathologica communications · 2025Article
- Neuroaxonal Degeneration as a Converging Mechanism in Motor Neuron Diseases (MNDs): Molecular Insights into RNA Dysregulation and Emerging Therapeutic Targets.International journal of molecular sciences · 2025Review
- Article
- Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS.Nature communications · 2025Article
- Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy.The Lancet. Neurology · 2025Review
30 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 6 institutions in 2 countries.
Funding
Abstract
Axonal dysfunction is a common phenotype in neurodegenerative disorders, including in amyotrophic lateral sclerosis (ALS), where the key pathological cell-type, the motor neuron (MN), has an axon extending up to a metre long. The maintenance of axonal function is a highly energy-demanding process, raising the question of whether MN cellular energetics is perturbed in ALS, and whether its recovery promotes axonal rescue. To address this, we undertook cellular and molecular interrogation of multiple patient-derived induced pluripotent stem cell lines and patient autopsy samples harbouring the most common ALS causing mutation, C9orf72. Using paired mutant and isogenic expansion-corrected controls, we show that C9orf72 MNs have shorter axons, impaired fast axonal transport of mitochondrial cargo, and altered mitochondrial bioenergetic function. RNAseq revealed reduced gene expression of mitochondrially encoded electron transport chain transcripts, with neuropathological analysis of C9orf72-ALS post-mortem tissue importantly confirming selective dysregulation of the mitochondrially encoded transcripts in ventral horn spinal MNs, but not in corresponding dorsal horn sensory neurons, with findings reflected at the protein level. Mitochondrial DNA copy number was unaltered, both in vitro and in human post-mortem tissue. Genetic manipulation of mitochondrial biogenesis in C9orf72 MNs corrected the bioenergetic deficit and also rescued the axonal length and transport phenotypes. Collectively, our data show that loss of mitochondrial function is a key mediator of axonal dysfunction in C9orf72-ALS, and that boosting MN bioenergetics is sufficient to restore axonal homeostasis, opening new potential therapeutic strategies for ALS that target mitochondrial function.
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