TorsinA protein degradation and autophagy in DYT1 dystonia

• Type of Material: Article
• Authors: Lisa M. Giles, Emory University; Lian Li, Emory University; Lih-Shen Chin, Emory University
• Language: English
• Date: 2009-01-01
• Publisher: Taylor & Francis: STM, Behavioural Science and Public Health Titles
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 Landes Bioscience
• Final Published Version (URL): https://www.landesbioscience.com/journals/autophagy/article/7173/?nocache=558748786
• Title of Journal or Parent Work: Autophagy
• ISSN: 1554-8627
• Volume: 5
• Issue: 1
• Start Page: 82
• End Page: 84
• Grant/Funding Information: 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: nuclear envelope; protein misfolding; Dystonia; torsinA; endoplasmic reticulum-associated degradation; protein quality control; autophagy; endoplasmic reticulum
• Research Categories: Health Sciences, General; Health Sciences, Pharmacology

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.