Amyloid-like oligomerization of AIMP2 contributes to alpha-synuclein interaction and Lewy-like inclusion
- 윤승필; 함상우; 김효정; 김동훈; 서보암; 김희정; 신정용; Mohamad Aasif Dar; 이금화; 이윤일; 김도연; 김성훈; 김희석; 신주호; 고한석; 이연종
- Issue Date
- AMER ASSOC ADVANCEMENT SCIENCE
- SCIENCE TRANSLATIONAL MEDICINE, v.12, no.569
- Journal Title
- SCIENCE TRANSLATIONAL MEDICINE
- Lewy bodies are pathological protein inclusions present in the brain of patients with Parkinsons disease (PD). These inclusions consist mainly of alpha-synuclein with associated proteins, such as parkin and its substrate aminoacyl transfer RNA synthetase complex-interacting multifunctional protein-2 (AIMP2). Although AIMP2 has been suggested to be toxic to dopamine neurons, its roles in alpha-synuclein aggregation and PD pathogenesis are largely unknown. Here, we found that AIMP2 exhibits a self-aggregating property. The AIMP2 aggregate serves as a seed to increase alpha-synuclein aggregation via specific and direct binding to the alpha-synuclein monomer. The coexpression of AIMP2 and alpha-synuclein in cell cultures and in vivo resulted in the rapid formation of alpha-synuclein aggregates with a corresponding increase in toxicity. Moreover, accumulated AIMP2 in mouse brain was largely redistributed to insoluble fractions, correlating with the alpha-synuclein pathology. Last, we found that alpha-synuclein preformed fibril (PFF) seeding, adult Parkin deletion, or oxidative stress triggered a redistribution of both AIMP2 and alpha-synuclein into insoluble fraction in cells and in vivo. Supporting the pathogenic role of AIMP2, AIMP2 knockdown ameliorated the alpha-synuclein aggregation and dopaminergic cell death in response to PFF or 6-hydroxydopamine treatment. Together, our results suggest that AIMP2 plays a pathological role in the aggregation of alpha-synuclein in mice. Because AIMP2 insolubility and coaggregation with alpha-synuclein have been seen in the PD Lewy body, targeting pathologic AIMP2 aggregation might be useful as a therapeutic strategy for neurodegenerative alpha-synucleinopathies.
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- College of Medicine > Department of Medicine > Journal Articles
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