title: Glucose regulated protein 78 diminishes α-synuclein neurotoxicity in a rat model of Parkinson disease.
abstract: Accumulation of human wild-type (wt) α-synuclein (α-syn) induces neurodegeneration in humans and in experimental rodent models of Parkinson disease (PD). It also leads to endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). We overexpressed glucose regulated protein 78, also known as BiP (GRP78/BiP), to test the hypothesis that this ER chaperone modulates the UPR, blocks apoptosis, and promotes the survival of nigral dopamine (DA) neurons in a rat model of PD induced by elevated level of human α-syn. We determined that α-syn activates ER stress mediators associated with pancreatic ER kinase-like ER kinase (PERK) and activating transcription factor-6 (ATF6) signaling pathways as well as proaoptotic CCAAT/-enhancer-binding protein homologous protein (CHOP) in nigral DA neurons. At the same time, overexpression of GRP78/BiP diminished α-syn neurotoxicity by down regulating ER stress mediators and the level of apoptosis, promoted survival of nigral tyrosine hydroxylase (TH) positive cells and resulted in higher levels of striatal DA, while eliminating amphetamine induced behavioral asymmetry. We also detected a complex between GRP78/BiP and α-syn that may contribute to prevention of the neurotoxicity caused by α-syn. Our data suggest that the molecular chaperone GRP78/BiP plays a neuroprotective role in α-syn-induced Parkinson-like neurodegeneration.
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida 32610, USA.
authors.forename: Marina S
authors.initials: MS
authors.lastname: Gorbatyuk
authors.forename: Arseniy
authors.initials: A
authors.lastname: Shabashvili
authors.forename: Weijun
authors.initials: W
authors.lastname: Chen
authors.forename: Craig
authors.initials: C
authors.lastname: Meyers
authors.forename: Layla F
authors.initials: LF
authors.lastname: Sullivan
authors.forename: Max
authors.initials: M
authors.lastname: Salganik
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Lin
authors.forename: Alfred S
authors.initials: AS
authors.lastname: Lewin
authors.forename: Nicholas
authors.initials: N
authors.lastname: Muzyczka
authors.forename: Oleg S
authors.initials: OS
authors.lastname: Gorbatyuk
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D015398:Signal Transduction; D013378:Substantia Nigra / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis; D056811:Unfolded Protein Response; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D000662:Amphetamines; D000091342:Endoplasmic Reticulum Chaperone BiP; D049452:Green Fluorescent Proteins; D006360:Heat-Shock Proteins; D018696:Neuroprotective Agents; D051742:Transcription Factor CHOP; D014446:Tyrosine 3-Monooxygenase; D051844:alpha-Synuclein; D019892:eIF-2 Kinase; C497113:Atf6 protein, rat; C497251:Ddit3 protein, rat; C000717247:HSPA5 protein, human