Spastin-interacting protein NA14/SSNA1 functions in cytokinesis and axon development.
Hereditary spastic paraplegias (HSPs) are a genetically diverse group of inherited neurological disorders (SPG1-72) with the cardinal feature of prominent lower-extremity spasticity due to a length-dependent axonopathy of corticospinal motor neurons. The most frequent form of autosomal dominant HSP results from mutations of the SPG4 gene product spastin. This is an ATPase associated with diverse cellular activities (AAA) protein that binds to and severs microtubules. While spastin participates in crucial cellular processes such as cytokinesis, endosomal tubulation, and axon development, its role in HSP pathogenesis remains unclear. Spastin interacts in cells with the NA14 protein, a major target for auto-antibodies in Sjögren's syndrome (nuclear autoantigen 1; SSNA1). Our analysis of endogenous spastin and NA14 proteins in HeLa cells and rat cortical neurons in primary culture revealed a clear distribution of both proteins to centrosomes, with NA14 localizing specifically to centrioles. Stable NA14 knockdown in cell lines dramatically affected cell division, in particular cytokinesis. Furthermore, overexpression of NA14 in neurons significantly increased axon outgrowth and branching, while also enhancing neuronal differentiation. We postulate that NA14 may act as an adaptor protein regulating spastin localization to centrosomes, temporally and spatially regulating the microtubule-severing activity of spastin that is particularly critical during the cell cycle and neuronal development.
Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
Uma
U
Goyal
Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
Benoît
B
Renvoisé
Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
Jaerak
J
Chang
Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
Craig
C
Blackstone
D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D002454:Cell Differentiation; D018385:Centrosome / Q000378:metabolism / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D048749:Cytokinesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D006801:Humans; D008870:Microtubules / Q000378:metabolism / Q000648:ultrastructure; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D000074181:Spastin
D001324:Autoantigens; C110204:NA14 nuclear autoantigen; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human