Amyloid-like oligomerization of AIMP2 contributes to α-synuclein interaction and Lewy-like inclusion
- Authors
- Ham, S.[Ham, S.]; Yun, S.P.[Yun, S.P.]; Kim, H.[Kim, H.]; Kim, D.[Kim, D.]; Seo, B.A.[Seo, B.A.]; Kim, H.[Kim, H.]; Shin, J.-Y.[Shin, J.-Y.]; Dar, M.A.[Dar, M.A.]; Lee, G.H.[Lee, G.H.]; Lee, Y.I.[Lee, Y.I.]; Kim, D.[Kim, D.]; Kim, S.[Kim, S.]; Kweon, H.-S.[Kweon, H.-S.]; Shin, J.-H.[Shin, J.-H.]; Ko, H.S.[Ko, H.S.]; Lee, Y.[Lee, Y.]
- Issue Date
- 11-Nov-2020
- Publisher
- American Association for the Advancement of Science
- Citation
- Science Translational Medicine, v.12, no.569
- Indexed
- SCIE
SCOPUS
- Journal Title
- Science Translational Medicine
- Volume
- 12
- Number
- 569
- URI
- https://scholarworks.bwise.kr/skku/handle/2021.sw.skku/6397
- DOI
- 10.1126/scitranslmed.aax0091
- ISSN
- 1946-6234
- Abstract
- Lewy bodies are pathological protein inclusions present in the brain of patients with Parkinson's disease (PD). These inclusions consist mainly of α-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 α-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 α-synuclein aggregation via specific and direct binding to the α-synuclein monomer. The coexpression of AIMP2 and α-synuclein in cell cultures and in vivo resulted in the rapid formation of α-synuclein aggregates with a corresponding increase in toxicity. Moreover, accumulated AIMP2 in mouse brain was largely redistributed to insoluble fractions, correlating with the α-synuclein pathology. Last, we found that α-synuclein preformed fibril (PFF) seeding, adult Parkin deletion, or oxidative stress triggered a redistribution of both AIMP2 and α-synuclein into insoluble fraction in cells and in vivo. Supporting the pathogenic role of AIMP2, AIMP2 knockdown ameliorated the α-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 α-synuclein in mice. Because AIMP2 insolubility and coaggregation with α-synuclein have been seen in the PD Lewy body, targeting pathologic AIMP2 aggregation might be useful as a therapeutic strategy for neurodegenerative α-synucleinopathies. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
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Collections - Medicine > Department of Medicine > 1. Journal Articles
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