ArticleHuman molecular genetics2014
Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers, 1 of them a synthesis that pooled it.
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Who cites it
75 citing papers in PubMed, 1 synthesis or guideline pooled it, 117 citations in OpenAlex.
- Pooled it
- Whole-exome sequencing reveals a novel frameshift and a recurrent nonsense SPG11 variant causing rare familial amyotrophic lateral sclerosis type 5 in two consanguineous Pakistani families.Molecular biology reports · 2026Article
- Cutting-edge treatments in amyotrophic lateral sclerosis: the role of molecular pathogenesis in targeted therapies.Stem cell research & therapy · 2025Review
- Review
- Exome sequencing reveals broad genetic heterogeneity for neuromuscular disorders in consanguineous Pakistani Families.European journal of human genetics : EJHG · 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
- Genetic Evaluation of Patients with Clinically Suspected Hereditary Spastic Paraplegia with Seven Novel Variants.Annals of Indian Academy of Neurology · 2025Article
- Clinical features and genotype in COQ4 associated hereditary spastic paraplegia: a case report and a literature reanalysis.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Review
- Hereditary spastic paraplegia with thin corpus callosum and SPG11 mutation: A neuropathological evaluation.Neuropathology : official journal of the Japanese Society of Neuropathology · 2025Article
- Transcriptomic analysis reinforces the implication of spatacsin in neuroinflammation and neurodevelopment.Scientific reports · 2025Article
- The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).Autophagy reports · 2025Review
- A novel mutation inPakistan journal of medical sciences · 2024Article
- AP2A2 mutation and defective endocytosis in a Malian family with hereditary spastic paraplegia.Neurobiology of disease · 2024Article
- Activation and Purification of ß-Glucocerebrosidase by Exploiting its Transporter LIMP-2 - Implications for Novel Treatment Strategies in Gaucher's and Parkinson's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Late-onset Krabbe disease presenting as spastic paraplegia - implications of GCase and CTSB/D.Annals of clinical and translational neurology · 2024Article
- Identification and analyses of exonic and copy number variants in spastic paraplegia.Scientific reports · 2024Article
- Exome sequencing in four families with neurodevelopmental disorders: genotype-phenotype correlation and identification of novel disease-causing variants in VPS13B and RELN.Molecular genetics and genomics : MGG · 2024Article
- Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias.International journal of molecular sciences · 2024Review
- Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients.Acta neuropathologica · 2024Article
- Clinically approved immunomodulators ameliorate behavioral changes in a mouse model of hereditary spastic paraplegia type 11.Frontiers in neuroscience · 2024Article
15 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hereditary spastic paraplegias are a group of inherited motor neuron diseases characterized by progressive paraparesis and spasticity. Mutations in the spastic paraplegia gene SPG11, encoding spatacsin, cause an autosomal-recessive disease trait; however, the precise knowledge about the role of spatacsin in neurons is very limited. We for the first time analyzed the expression and function of spatacsin in human forebrain neurons derived from human pluripotent stem cells including lines from two SPG11 patients and two controls. SPG11 patients'-derived neurons exhibited downregulation of specific axonal-related genes, decreased neurite complexity and accumulation of membranous bodies within axonal processes. Altogether, these data point towards axonal pathologies in human neurons with SPG11 mutations. To further corroborate spatacsin function, we investigated human pluripotent stem cell-derived neurons and mouse cortical neurons. In these cells, spatacsin was located in axons and dendrites. It colocalized with cytoskeletal and synaptic vesicle (SV) markers and was present in synaptosomes. Knockdown of spatacsin in mouse cortical neurons evidenced that the loss of function of spatacsin leads to axonal instability by downregulation of acetylated tubulin. Finally, time-lapse assays performed in SPG11 patients'-derived neurons and spatacsin-silenced mouse neurons highlighted a reduction in the anterograde vesicle trafficking indicative of impaired axonal transport. By employing SPG11 patient-derived forebrain neurons and mouse cortical neurons, this study provides the first evidence that SPG11 is implicated in axonal maintenance and cargo trafficking. Understanding the cellular functions of spatacsin will allow deciphering mechanisms of motor cortex dysfunction in autosomal-recessive hereditary spastic paraplegia.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.