ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2008
Hereditary spastic paraplegia-associated mutations in the NIPA1 gene and its Caenorhabditis elegans homolog trigger neural degeneration in vitro and in vivo through a gain-of-function mechanism.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 42 citations in OpenAlex.
- The SLC-ome of membrane transport: from molecular discovery to physiology and clinical applications.Physiological reviews · 2026Review
- Mechanistic studies of the human NIPA2 transporter.Nature communications · 2026Article
- Loss-of-function mutation in DDX53 associated with hereditary spastic paraplegia-like disorder.Journal of molecular medicine (Berlin, Germany) · 2024Article
- Review
- Clinical and genetic characterization of NIPA1 mutations in a Taiwanese cohort with hereditary spastic paraplegia.Annals of clinical and translational neurology · 2023Review
- Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias.International journal of molecular sciences · 2022Article
- Clinical and Genetic Features of Chinese Patients WithFrontiers in genetics · 2022Article
- A novel de novo NIPA1 missense mutation associated to hereditary spastic paraplegia.Journal of human genetics · 2021Article
- Is NIPA1-associated hereditary spastic paraplegia always 'pure'? Further evidence of motor neurone disease and epilepsy as rare manifestations.Neurogenetics · 2020Article
- The 15q11.2 BP1-BP2 Microdeletion (International journal of molecular sciences · 2020Review
- Sensory neuropathy-causing mutations in ATL3 affect ER-mitochondria contact sites and impair axonal mitochondrial distribution.Human molecular genetics · 2019Article
- NeurodegenERation: The Central Role for ER Contacts in Neuronal Function and Axonopathy, Lessons From Hereditary Spastic Paraplegias and Related Diseases.Frontiers in neuroscience · 2019Review
- Comparison of γ-Aminobutyric Acid, Type A (GABAA), Receptor αβγ and αβδ Expression Using Flow Cytometry and Electrophysiology: EVIDENCE FOR ALTERNATIVE SUBUNIT STOICHIOMETRIES AND ARRANGEMENTS.The Journal of biological chemistry · 2016Article
- Functional study of NIPA2 mutations identified from the patients with childhood absence epilepsy.PloS one · 2014Article
- Worming forward: amyotrophic lateral sclerosis toxicity mechanisms and genetic interactions in Caenorhabditis elegans.Frontiers in genetics · 2014Review
- Pathogenesis of autosomal dominant hereditary spastic paraplegia (SPG6) revealed by a rat model.Journal of neuropathology and experimental neurology · 2013Article
- REEPing the benefits of an animal model of hereditary spastic paraplegia.The Journal of clinical investigation · 2013Article
- Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms.Acta neuropathologica · 2013Review
- Hereditary spastic paraplegia-causing mutations in atlastin-1 interfere with BMPRII trafficking.Molecular and cellular neurosciences · 2013Article
- NIPA2 located in 15q11.2 is mutated in patients with childhood absence epilepsy.Human genetics · 2012Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
We studied the consequences of expression of wild-type (WT) human NIPA1 and two mutant forms of NIPA1 with known HSP-associated mutations (T45R and G106R) on cultured rat cortical neurons and using equivalent substitutions in the Caenorhabditis elegans NIPA1 homolog CeNIPA. WT NIPA1 localized in transfected neuronal and non-neuronal cells to the Golgi complex, a subset of synaptic vesicles, to a subset of early endosomes, and plasma cell membrane. Mutant NIPA1 accumulated in the endoplasmic reticulum (ER) triggering ER stress and features of apoptotic cell death. Flow cytometric analysis of NIPA1 surface expression demonstrated relatively intact trafficking of mutant forms and only the T45R mutant exhibited modestly reduced patterns of surface expression without evidence for a dominant-negative effect. In vivo pan-neuronal expression of the WT C. elegans NIPA1 homolog (CeNIPA) was well tolerated, with no obvious impact on neuronal morphology or behavior. In striking contrast, expression of CeNIPA bearing HSP-associated mutations caused a progressive neural degeneration and a clear motor phenotype. Neuronal loss in these animals began at day 7 and by day 9 animals were completely paralyzed. These effects appeared to arise from activation of the apoptotic program triggered by unfolded protein response (UPR), as we observed marked modifications of motor and cellular phenotype when mutant NIPA1 was expressed in caspase (ced-3)- and UPR (xbp-1)-deficient backgrounds. We propose that HSP-associated mutations in NIPA1 lead to cellular and functional deficits through a gain-of-function mechanism supporting the ER accumulation of toxic NIPA1 proteins.
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