title: Formation and removal of alpha-synuclein aggregates in cells exposed to mitochondrial inhibitors.
abstract: Mitochondrial dysfunction has been associated with Parkinson's disease. However, the role of mitochondrial defects in the formation of Lewy bodies, a pathological hallmark of Parkinson's disease has not been addressed directly. In this report, we investigated the effects of inhibitors of the mitochondrial electron-transport chain on the aggregation of alpha-synuclein, a major protein component of Lewy bodies. Treatment with rotenone, an inhibitor of complex I, resulted in an increase of detergent-resistant alpha-synuclein aggregates and a reduction in ATP level. Another inhibitor of the electron-transport chain, oligomycin, also showed temporal correlation between the formation of aggregates and ATP reduction. Microscopic analyses showed a progressive evolution of small aggregates of alpha-synuclein to a large perinuclear inclusion body. The inclusions were co-stained with ubiquitin, 20 S proteasome, gamma-tubulin, and vimentin. The perinuclear inclusion bodies, but not the small cytoplasmic aggregates, were thioflavin S-positive, suggesting the amyloid-like conformation. Interestingly, the aggregates disappeared when the cells were replenished with inhibitor-free medium. Disappearance of aggregates coincided with the recovery of mitochondrial metabolism and was partially inhibited by proteasome inhibitors. These results suggest that the formation of alpha-synuclein inclusions could be initiated by an impaired mitochondrial function and be reversed by restoring normal mitochondrial metabolism.
authors.affiliation: Parkinson's Institute, Sunnyvale, California 94089, USA.
authors.forename: He-Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Shin
authors.forename: Chan
authors.initials: C
authors.lastname: Choi
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D003546:Cysteine Endopeptidases / Q000494:pharmacology; D004579:Electron Transport; D004583:Electrons; D006801:Humans; D020287:In Situ Nick-End Labeling; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D051843:Synucleins; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D025801:Ubiquitin / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology; D014746:Vimentin / Q000378:metabolism; D051844:alpha-Synuclein
chemical_list: D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051843:Synucleins; D014404:Tubulin; D025801:Ubiquitin; D014475:Uncoupling Agents; D014746:Vimentin; D051844:alpha-Synuclein; D012402:Rotenone; D000255:Adenosine Triphosphate; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex