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

Sangwoo Ham, Seung Pil Yun, Hyojung Kim, Donghoon Kim, Bo Am Seo, Heejeong Kim, Jeong Yong Shin, Mohamad Aasif Dar, Gum Hwa Lee, Yun Il Lee, Doyeun Kim, Sunghoon Kim, Hee Seok Kweon, Joo Ho Shin, Han Seok Ko, Yunjong Lee

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11 Citations (Scopus)


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.

Original languageEnglish
Article numbereaax0091
JournalScience Translational Medicine
Issue number569
Publication statusPublished - 2020 Nov 11

Bibliographical note

Funding Information:
This research was supported by grants (2017M3C7A1043848 to Y.L.) of the National Research Foundation (NRF) funded by the Ministry of Science, ICT, and Future Planning (MSIP) and also supported by the Korea Basic Science Institute under the R&D program (project no. C030440 to Y.L. and H.-S.K.) supervised by the Ministry of Science and ICT, Republic of Korea. This work was also supported by grants from the NIH/NINDS NS38377 Morris K. Udall PD Research Center and NIH/NINDS NS107404 and NS098006 (to H.S.K.). We are also grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona for the provision of human biological materials. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for PD and Related Disorders), the National Institute of Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001 to the Arizona PD Consortium), and the Michael J. Fox Foundation for Parkinson's Research.

Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

All Science Journal Classification (ASJC) codes

  • Medicine(all)


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