Accumulation of Toxic α-Synuclein Oligomer within Endoplasmic Reticulum Occurs in α-SynucleinopathyIn Vivo
Open Access
- 7 March 2012
- journal article
- research article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 32 (10), 3301-3305
- https://doi.org/10.1523/jneurosci.5368-11.2012
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 usingin vitrosystems are not generally seen to be associated with α-synucleinopathyin 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.Keywords
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