Accumulation of Toxic α-Synuclein Oligomer within Endoplasmic Reticulum Occurs in α-SynucleinopathyIn Vivo
Year: 2012
Type: article
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.
Source: Journal of Neuroscience
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: G1378659243, Preclinical Evaluation of Celastrol, an Inducer of HSP, in alpha-Syn Tg mice, Pathological interactions of a-syn, mitochondria, and pesticides in PD models, SYNUCLEINS--CELL BIOLOGY AND TRANSGENIC MICE, Abeta and Monoaminergic Neurodegeneration in Transgenic Mouse Models of AD, Neurodegenerative interactions in conditional LRRK2 Tg models, Synucleins: Cell biology and transgenic mice, Morris K. Udall Centers of Excellence for Parkinson's Disease Research (P50), Conditional Uch-L1 knockout mice, G6948929462, Synucleins: Cell biology and transgenic mice
OpenAlex ID: W1992241406