Glucose Regulated Protein 78 Diminishes α-Synuclein Neurotoxicity in a Rat Model of Parkinson Disease

Accumulation of human wild-type (wt) alpha-synuclein (alpha-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 alpha-syn. We determined that alpha-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 alpha-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 alpha-syn that may contribute to prevention of the neurotoxicity caused by alpha-syn. Our data suggest that the molecular chaperone GRP78/BiP plays a neuroprotective role in alpha-syn-induced Parkinson-like neurodegeneration. Received 16 September 2011; accepted 30 January 2012; advance online publication 20 March 2012. doi:10.1038/mt.2012.28