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Author Notes:

To whom correspondence should be addressed: Lih-Shen Chin, PhD, Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322-3090, Telephone: 404-727-5987, Fax: 404-727-0365, Email: chinl@pharm.emory.edu

Subjects:

Research Funding:

This work was supported by National Institutes of Health grants NS054334 (L.M.G.), ES015813 (L.L.), GM082828 (L.L.), and NS050650 (L.S.C.).

Keywords:

  • Dystonia
  • autophagy
  • torsinA
  • endoplasmic reticulum-associated degradation
  • endoplasmic reticulum
  • nuclear envelope
  • protein misfolding
  • protein quality control

TorsinA protein degradation and autophagy in DYT1 dystonia

Tools:

Journal Title:

Autophagy

Volume:

Volume 5, Number 1

Publisher:

, Pages 82-84

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Early-onset generalized dystonia (DYT1) is a debilitating neurological disorder characterized by involuntary movements and sustained muscle spasms. DYT1 dystonia has been associated with two mutations in torsinA that result in the deletion of a single glutamate residue (torsinA ΔE) and six amino-acid residues (torsinA Δ323-8). We recently revealed that torsinA, a peripheral membrane protein, which resides predominantly in the lumen of the endoplasmic reticulum (ER) and nuclear envelope (NE), is a long-lived protein whose turnover is mediated by basal autophagy. Dystonia-associated torsinA ΔE and torsinA Δ323-8 mutant proteins show enhanced retention in the NE and accelerated degradation by both the proteasome and autophagy. Our results raise the possibility that the monomeric form of torsinA mutant proteins is cleared by proteasome-mediated ER-associated degradation (ERAD), whereas the oligomeric and aggregated forms of torsinA mutant proteins are cleared by ER stress-induced autophagy. Our findings provide new insights into the pathogenic mechanism of torsinA ΔE and torsinA Δ323-8 mutations in dystonia and emphasize the need for a mechanistic understanding of the role of autophagy in protein quality control in the ER and NE compartments.

Copyright information:

© 2009 Landes Bioscience

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