title: Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo.
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.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Colla
authors.forename: Poul H
authors.initials: PH
authors.lastname: Jensen
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.forename: Charles
authors.initials: C
authors.lastname: Glabe
authors.forename: Michael K
authors.initials: MK
authors.lastname: Lee
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000378:metabolism* / Q000633:toxicity*; D018384:Oxidative Stress / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism* / Q000633:toxicity*
chemical_list: D009841:Oligonucleotides; D051844:alpha-Synuclein