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Mutant SOD 1 inhibits ER ‐Golgi transport in amyotrophic lateral sclerosis
Author(s) -
Atkin Julie D.,
Farg Manal A.,
Soo Kai Ying,
Walker Adam K.,
Halloran Mark,
Turner Bradley J.,
Nagley Phillip,
Horne Malcolm K.
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12493
Subject(s) - golgi apparatus , endoplasmic reticulum , microbiology and biotechnology , unfolded protein response , sod1 , transport protein , copii , biology , fragmentation (computing) , chemistry , secretory pathway , superoxide dismutase , biochemistry , oxidative stress , ecology
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.Cu/Zn‐superoxide dismutase (SOD1) is misfolded in familial and sporadic Amyotrophic Lateral Sclerosis, but it is unclear how this triggers endoplasmic reticulum (ER) stress and other cellular events. Here, we show that mutant SOD1 inhibits protein transport from the ER to Golgi apparatus prior to ER stress, Golgi fragmentation and apoptosis, and restoration of transport prevents inclusion formation and apoptosis. COPII: coatomer coat protein II.