Journal
NEUROBIOLOGY OF DISEASE
Volume 76, Issue -, Pages 112-125Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2015.02.005
Keywords
alpha-Synuclein; Unfolded protein response; ATF6; XBP1; Endoplasmic reticulum-associated degradation; COPII; Parkinson's disease; Neurodegeneration
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Funding
- National Institute of Mental Health [RO1MH075020]
- National Institute of Aging [RO1AG28108]
- National Institute of neurological Disorders and Stroke [RO1NS060041]
- Parkinson's Disease Foundation (PDF.org)
- NIH National Cancer Institute [P30CA051008, P30-CA051008]
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The unfolded protein response (UPR) monitors the folding environment within the endoplasmic reticulum (ER). Accumulation of misfolded proteins within the ER activates the UPR resulting in the execution of adaptive or non-adaptive signaling pathways. alpha-Synudein (alpha-syn) whose accumulation and aggregation define the pathobiology of Parkinson's disease (PD) has been shown to inhibit ER-Golgi transit of COPII vesicles. ATF6, a protective branch of the UPR, is processed via COPII mediated ER-Golgi transit following its activation via ER stress. Using cellular PD models together with biochemical reconstitution assays, we showed that alpha-syn inhibited processing of ATF6 directly through physical interactions and indirectly through restricted incorporation into COPII vesicles. Impaired ATF6 signaling was accompanied by decreased ER-associated degradation (ERAD) function and increased pro-apoptotic signaling. The mechanism by which alpha-syn inhibits ATF6 signaling expands our understanding of the role ER stress and the UPR play in neurodegenerative diseases such as PD. (C) 2015 Elsevier Inc. All rights reserved.
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