Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo

Emanuela Colla, Poul H. Jensen, Olga Pletnikova, Juan C. Troncoso, Charles Glabe, Michael K. Lee

Research output: Contribution to journalArticlepeer-review

179 Scopus citations

Abstract

In Parkinson's disease (PD) and other α-synucleinopathies, prefibrillar α-synuclein (αS) oligomer is implicated in the pathogenesis. However, toxic αS oligomers observed using in vitro systems are not generally seen to be associated with α-synucleinopathy in vivo. Thus, the pathologic significance of αS oligomers to αS neurotoxicity is unknown. Herein, we show that, αS that accumulate within endoplasmic reticulum (ER)/microsome forms toxic oligomers in mouse and human brain with the α-synucleinopathy. In the mouse model of α-synucleinopathy, αS oligomers initially form before the onset of disease and continue to accumulate with the disease progression. Significantly, treatment of αS transgenic mice with Salubrinal, an anti-ER stress compound that delays the onset of disease, reduces ER accumulation of αS oligomers. These results indicate that αS oligomers with toxic conformation accumulate in ER, and αS oligomerdependent ER stress is pathologically relevant for PD.

Original languageEnglish (US)
Pages (from-to)3301-3305
Number of pages5
JournalJournal of Neuroscience
Volume32
Issue number10
DOIs
StatePublished - Mar 7 2012

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