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J Neurosci. 2012 Mar 7;32(10):3301-5. doi: 10.1523/JNEUROSCI.5368-11.2012.

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

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1
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

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 oligomer-dependent ER stress is pathologically relevant for PD.

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PMID:
22399752
PMCID:
PMC3548448
DOI:
10.1523/JNEUROSCI.5368-11.2012
[Indexed for MEDLINE]
Free PMC Article

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