Inhibition of N-linked glycosylation prevents inclusion formation by the dystonia-related mutant form of torsinA

被引:26
作者
Bragg, DC
Kaufman, CA
Kock, N
Breakefield, XO
机构
[1] Massachusetts Gen Hosp, Dept Neurol, Mol Neurogenet Unit, Boston, MA 02129 USA
[2] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02129 USA
[3] Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02114 USA
关键词
D O I
10.1016/j.mcn.2004.07.009
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Most cases of early-onset torsion dystonia are associated with a mutation in the DYT1 gene that results in the loss of a glutamic acid residue in the carboxy terminus of the encoded protein, torsinA. When overexpressed in cultured cells, wild-type torsinA distributes diffusely throughout the endoplasmic reticulum (ER), while the dystonia-related mutant, torsinADeltaE, accumulates within multilamellar membrane inclusions. Here we show that inclusion formation requires the addition of an N-linked oligosaccharide to one of two asparagine residues within the ATP-binding domain of the mutant protein. In the absence of this modification, overexpressed torsinADeltaE was localized diffusely throughout the cell in a reticular pattern resembling that of wild-type torsinA. In contrast, the localization of wild-type torsinA did not appear to vary with its glycosylation state. These results thus indicate that torsinADeltaE must achieve a specific conformation to induce formation of intracellular membrane inclusions. (C) 2004 Elsevier Inc. All rights reserved.
引用
收藏
页码:417 / 426
页数:10
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