title: A molecular mechanism underlying the neural-specific defect in torsinA mutant mice.
abstract: A striking but poorly understood feature of many diseases is the unique involvement of neural tissue. One example is the CNS-specific disorder DYT1 dystonia, caused by a 3-bp deletion ("DeltaE") in the widely expressed gene TOR1A. Disease mutant knockin mice (Tor1a(DeltaE/DeltaE)) exhibit disrupted nuclear membranes selectively in neurons, mimicking the tissue specificity of the human disease and providing a model system in which to dissect the mechanisms underlying neural selectivity. Our in vivo studies demonstrate that lamina-associated polypeptide 1 (LAP1) and torsinB function with torsinA to maintain normal nuclear membrane morphology. Moreover, we show that nonneuronal cells express dramatically higher levels of torsinB and that RNAi-mediated depletion of torsinB (but not other torsin family members) causes nuclear membrane abnormalities in Tor1a(DeltaE/DeltaE) nonneuronal cells. The Tor1a(DeltaE/DeltaE) neural selective phenotype therefore arises because high levels of torsinB protect nonneuronal cells from the consequences of torsinA dysfunction, demonstrating how tissue specificity may result from differential susceptibility of cell types to insults that disrupt ubiquitous biological pathways.
authors.affiliation: Department of Neurology and Integrated Graduate Program in Cellular, Molecular, Structural, and Genetic Studies, Columbia University, New York, NY 10032, USA.
authors.forename: Connie E
authors.initials: CE
authors.lastname: Kim
authors.forename: Alex
authors.initials: A
authors.lastname: Perez
authors.forename: Guy
authors.initials: G
authors.lastname: Perkins
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.forename: William T
authors.initials: WT
authors.lastname: Dauer
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D034622:RNA Interference
chemical_list: C491548:Dyt1 protein, mouse; D018832:Molecular Chaperones; C400325:Tor1b protein, mouse
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