ArticleHuman molecular genetics2018
Impaired mitochondrial dynamics underlie axonal defects in hereditary spastic paraplegias.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 50 citations in OpenAlex.
- MK4 Repositioning for IAHSP: OvercomingACS chemical neuroscience · 2026Article
- Rescue of mitochondrial and neurite pathology inBrain communications · 2026Article
- Small peptide P110 mitigates axonal degeneration of SPG15 patient iPSC-derived neurons by targeting mitochondrial dysfunction.Neurobiology of disease · 2025Article
- Neurodevelopmental Implications Underpinning Hereditary Spastic Paraplegia.CNS neuroscience & therapeutics · 2025Review
- Epigallocatechin gallate attenuated high glucose-induced pancreatic beta cell dysfunction by modulating DRP1-mediated mitochondrial apoptosis pathways.Scientific reports · 2024Article
- An Automated Imaging-Based Screen for Genetic Modulators of ER Organisation in Cultured Human Cells.Cells · 2024Article
- Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias.International journal of molecular sciences · 2024Review
- Metabolite profile in hereditary spastic paraplegia analyzed using magnetic resonance spectroscopy: a cross-sectional analysis in a longitudinal study.Frontiers in neuroscience · 2024Article
- Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients.Orphanet journal of rare diseases · 2023Article
- Hereditary spastic paraplegia (SPG 48) with deafness and azoospermia: A case report.Frontiers in neurology · 2023Article
- Pharmacological rescue of mitochondrial and neuronal defects inFrontiers in neuroscience · 2023Article
- Inhibiting mitochondrial fission rescues degeneration in hereditary spastic paraplegia neurons.Brain : a journal of neurology · 2022Article
- Article
- TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia.Brain : a journal of neurology · 2022Article
- Mitochondrial Quality and Quantity Control: Mitophagy Is a Potential Therapeutic Target for Ischemic Stroke.Molecular neurobiology · 2022Review
- Monitoring Axonal Degeneration in Human Pluripotent Stem Cell Models of Hereditary Spastic Paraplegias.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Role of adaptin protein complexes in intracellular trafficking and their impact on diseases.Bioengineered · 2021Article
- Stem Cell Models and Gene Targeting for Human Motor Neuron Diseases.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Hereditary Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery.Brain sciences · 2021Review
- MFN2 Deficiency Impairs Mitochondrial Transport and Downregulates Motor Protein Expression in Human Spinal Motor Neurons.Frontiers in molecular neuroscience · 2021Article
Corrections and comments
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Authors and funding
7 authors at 6 institutions in 2 countries.
Funding
Abstract
Mechanisms by which long corticospinal axons degenerate in hereditary spastic paraplegia (HSP) are largely unknown. Here, we have generated induced pluripotent stem cells (iPSCs) from patients with two autosomal recessive forms of HSP, SPG15 and SPG48, which are caused by mutations in the ZFYVE26 and AP5Z1 genes encoding proteins in the same complex, the spastizin and AP5Z1 proteins, respectively. In patient iPSC-derived telencephalic glutamatergic and midbrain dopaminergic neurons, neurite number, length and branching are significantly reduced, recapitulating disease-specific phenotypes. We analyzed mitochondrial morphology and noted a significant reduction in both mitochondrial length and their densities within axons of these HSP neurons. Mitochondrial membrane potential was also decreased, confirming functional mitochondrial defects. Notably, mdivi-1, an inhibitor of the mitochondrial fission GTPase DRP1, rescues mitochondrial morphology defects and suppresses the impairment in neurite outgrowth and late-onset apoptosis in HSP neurons. Furthermore, knockdown of these HSP genes causes similar axonal defects, also mitigated by treatment with mdivi-1. Finally, neurite outgrowth defects in SPG15 and SPG48 cortical neurons can be rescued by knocking down DRP1 directly. Thus, abnormal mitochondrial morphology caused by an imbalance of mitochondrial fission and fusion underlies specific axonal defects and serves as a potential therapeutic target for SPG15 and SPG48.
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Registered trials
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