Journal
JOURNAL OF NEUROSCIENCE
Volume 32, Issue 10, Pages 3301-3305Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5368-11.2012
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Funding
- NIH [NS038065, NS0380377, NS055776, ES017384]
- Lundbeck Foundation
- European Community
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In Parkinson's disease (PD) and other alpha-synucleinopathies, prefibrillar alpha-synuclein (alpha S) oligomer is implicated in the pathogenesis. However, toxic alpha S oligomers observed using in vitro systems are not generally seen to be associated with alpha-synucleinopathy in vivo. Thus, the pathologic significance of alpha S oligomers to alpha S neurotoxicity is unknown. Herein, we show that, alpha S that accumulate within endoplasmic reticulum (ER)/microsome forms toxic oligomers in mouse and human brain with the alpha-synucleinopathy. In the mouse model of alpha-synucleinopathy, alpha S oligomers initially form before the onset of disease and continue to accumulate with the disease progression. Significantly, treatment of alpha S transgenic mice with Salubrinal, an anti-ER stress compound that delays the onset of disease, reduces ER accumulation of alpha S oligomers. These results indicate that alpha S oligomers with toxic conformation accumulate in ER, and alpha S oligomer-dependent ER stress is pathologically relevant for PD.
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