Dystonia-causing mutant torsinA inhibits cell adhesion and neurite extension through interference with cytoskeletal dynamics.
Early onset torsion dystonia is a movement disorder inherited as an autosomal dominant syndrome with reduced penetrance. Symptoms appear to result from altered neuronal circuitry within the brain with no evidence of neuronal loss. Most cases are caused by loss of a glutamic acid residue in the AAA+ chaperone protein, torsinA, encoded in the DYT1 gene. In this study, torsinA was found to move in conjunction with vimentin in three cell culture paradigms-recovery from microtubule depolymerization, expression of a dominant-negative form of kinesin light chain and respreading after trypsinization. Co-immune precipitation studies revealed association between vimentin and torsinA in a complex including other cytoskeletal elements, actin and tubulin, as well as two proteins previously shown to interact with torsinA-the motor protein, kinesin light chain 1, and the nuclear envelope protein, LAP1. Morphologic and functional differences related to vimentin were noted in primary fibroblasts from patients carrying this DYT1 mutation as compared with controls, including an increased perinuclear concentration of vimentin and a delayed rate of adhesion to the substratum. Overexpression of mutant torsinA inhibited neurite extension in human neuroblastoma cells, with torsinA and vimentin immunoreactivity enriched in the perinuclear region and in cytoplasmic inclusions. Collectively, these studies suggest that mutant torsinA interferes with cytoskeletal events involving vimentin, possibly by restricting movement of these particles/filaments, and hence may affect development of neuronal pathways in the brain.
Hewett
Jeffrey W
JW
Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA 02114, USA.
Zeng
Juan
J
Niland
Brian P
BP
Bragg
D Cristopher
DC
Breakefield
Xandra O
XO
D000199:Actins / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000502:physiology; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism / Q000648:ultrastructure; D003595:Cytoplasmic Streaming / Q000502:physiology; D003599:Cytoskeleton / Q000378:metabolism*; D004422:Dystonia Musculorum Deformans / Q000378:metabolism / Q000503:physiopathology; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D016547:Kinesins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000502:physiology*; D016501:Neurites / Q000378:metabolism* / Q000648:ultrastructure; D014404:Tubulin / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism*
D000199:Actins; D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D008869:Microtubule-Associated Proteins; D018832:Molecular Chaperones; C108175:TOR1A protein, human; D014404:Tubulin; D014746:Vimentin; D016547:Kinesins