Formation and removal of alpha-synuclein aggregates in cells exposed to mitochondrial inhibitors

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 t...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-02, Vol.277 (7), p.5411-5417
Main Authors: Lee, He-Jin, Shin, Soon Young, Choi, Chan, Lee, Young Han, Lee, Seung-Jae
Format: Article
Language:English
Subjects:
a-Synuclein
Adenosine Triphosphate - metabolism
alpha-Synuclein
Animals
Blotting, Western
COS Cells
Cysteine Endopeptidases - pharmacology
Electron Transport
Electrons
Humans
In Situ Nick-End Labeling
Microscopy, Fluorescence
Mitochondria - metabolism
Multienzyme Complexes - pharmacology
Nerve Tissue Proteins - chemistry
Nerve Tissue Proteins - metabolism
Proteasome Endopeptidase Complex
Protein Conformation
Recombinant Proteins - metabolism
rotenone
Rotenone - pharmacology
Synucleins
Time Factors
Tubulin - metabolism
Ubiquitin - pharmacology
Uncoupling Agents - pharmacology
Vimentin - metabolism
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Summary: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.
ISSN:0021-9258
DOI:10.1074/jbc.M105326200