Mutant SOD1 inhibits ER-Golgi transport in amyotrophic lateral sclerosis

Julie Atkin, Manal A Farg, Kai-Ying Soo, Adam K Walker, Mark Halloran, Bradley J Turner, Phillip Nagley, Malcolm Kenneth Horne

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58 Citations (Scopus)

Abstract

Cu/Zn-superoxide dismutase (SOD1) is misfolded in familial and sporadic Amyotrophic Lateral Sclerosis (ALS), but it is not clear how this triggers endoplasmic reticulum (ER) stress or other pathogenic processes. Here we demonstrate that mutant SOD1 (mSOD1) is predominantly found in the cytoplasm in neuronal cells. Furthermore, we show that mSOD1 inhibits secretory protein transport from the ER to Golgi apparatus. ER-Golgi transport is linked to ER stress, Golgi fragmentation and axonal transport and we also show that inhibition of ER-Golgi trafficking preceded ER stress, Golgi fragmentation, protein aggregation and apoptosis in cells expressing mSOD1. Restoration of ER-Golgi transport by over-expression of coatomer coat protein II (COPII) subunit Sar1 protected against inclusion formation and apoptosis, thus linking dysfunction in ER-Golgi transport to cellular pathology. These findings thus link several cellular events in ALS into a single mechanism occurring early in mSOD1 expressing cells. This article is protected by copyright. All rights reserved.
Original languageEnglish
Pages (from-to)190 - 204
Number of pages15
JournalJournal of Neurochemistry
Volume129
Issue number1
DOIs
Publication statusPublished - 2014

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