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J Neurochem. 2011 Feb;116(4):588-605. doi: 10.1111/j.1471-4159.2010.07143.x. Epub 2011 Jan 19.

Induction of the unfolded protein response by α-synuclein in experimental models of Parkinson's disease.

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1
Division of Pharmacology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy. bellucci@med.unibs.it

Abstract

Accumulation of misfolded proteins in the endoplasmic reticulum (ER) is the main event leading to the induction of the ER stress-related unfolded protein response (UPR). Recent postmortem evaluation, showing that the UPR pathway is activated in nigral dopaminergic neurons bearing α-synuclein inclusions in the brain of Parkinson's disease (PD) patients, suggests that the activation of the UPR may be induced by the accumulation of α-synuclein. In this study, we show that the misfolded protein-sensor/UPR activator glucose-regulated protein 78/immunoglobulin heavy chain-binding protein was bound to α-synuclein and was increased in 'in vitro' and 'in vivo' models showing aggregated α-synuclein accumulation. Moreover, α-synuclein accumulation induced the expression of the UPR-related activating transcription factor 4/cAMP-responsive element-2. These findings indicate that activation of the UPR pathway in the PD brain is associated with α-synuclein accumulation occurring in part within the ER.

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