title: Mutant SOD1 inhibits ER-Golgi transport in amyotrophic lateral sclerosis.
abstract: Cu/Zn-superoxide dismutase is misfolded in familial and sporadic amyotrophic lateral sclerosis, 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 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 amyotrophic lateral sclerosis into a single mechanism occurring early in mSOD1 expressing cells.
authors.affiliation: Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, Australia; Department of Florey Neuroscience, University of Melbourne, Parkville, Melbourne, Australia.
authors.forename: Julie D
authors.initials: JD
authors.lastname: Atkin
authors.forename: Manal A
authors.initials: MA
authors.lastname: Farg
authors.forename: Kai Ying
authors.initials: KY
authors.lastname: Soo
authors.forename: Adam K
authors.initials: AK
authors.lastname: Walker
authors.forename: Mark
authors.initials: M
authors.lastname: Halloran
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Turner
authors.forename: Phillip
authors.initials: P
authors.lastname: Nagley
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Horne
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: ER-Golgi transport; amyotrophic lateral sclerosis; neurodegeneration