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Amyloid-like oligomerization of AIMP2 contributes to alpha-synuclein interaction and Lewy-like inclusion

Title
Amyloid-like oligomerization of AIMP2 contributes to alpha-synuclein interaction and Lewy-like inclusion
Authors
Ham, SangwooYun, Seung PilKim, HyojungKim, DonghoonSeo, Bo AmKim, HeejeongShin, Jeong-YongDar, MohamadLee, Gum HwaLee, Yun IlKim, DoyeunKim, SunghoonKweon, Hee-SeokShin, Joo-HoKo, Han SeokLee, Yunjong
DGIST Authors
Lee, Yun Il
Issue Date
2020-11
Citation
Science Translational Medicine, 12(569), eaax0091
Type
Article
Article Type
Article
Keywords
RECESSIVE JUVENILE PARKINSONISMRNA SYNTHETASE COFACTORDOWN-REGULATIONBODY FORMATIONDISEASEPROTEINAGGREGATIONNEURODEGENERATIONPHOSPHORYLATIONBODIES
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
URI
http://hdl.handle.net/20.500.11750/12770
DOI
10.1126/scitranslmed.aax0091
Publisher
American Association for the Advancement of Science
Related Researcher
Files:
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Collection:
Division of Biotechnology1. Journal Articles


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