Glucose regulated protein 78 diminishes α-synuclein neurotoxicity in a rat model of Parkinson disease

Mol Ther. 2012 Jul;20(7):1327-37. doi: 10.1038/mt.2012.28. Epub 2012 Mar 20.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / metabolism
  • Amphetamines / pharmacology
  • Animals
  • Apoptosis
  • Dependovirus / genetics
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress*
  • Genetic Vectors
  • Green Fluorescent Proteins / genetics
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Neuroprotective Agents / metabolism*
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Rats
  • Signal Transduction
  • Substantia Nigra / metabolism
  • Transcription Factor CHOP / metabolism
  • Tyrosine 3-Monooxygenase / biosynthesis
  • Unfolded Protein Response*
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*
  • eIF-2 Kinase / metabolism


  • Activating Transcription Factor 6
  • Amphetamines
  • Atf6 protein, rat
  • Ddit3 protein, rat
  • Heat-Shock Proteins
  • Neuroprotective Agents
  • alpha-Synuclein
  • Transcription Factor CHOP
  • Green Fluorescent Proteins
  • Tyrosine 3-Monooxygenase
  • PERK kinase
  • eIF-2 Kinase
  • molecular chaperone GRP78