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

• Published in: Science translational medicine Vol. 12; no. 569
• Main Authors: Ham, Sangwoo, Yun, Seung Pil, Kim, Hyojung, Kim, Donghoon, Seo, Bo Am, Kim, Heejeong, Shin, Jeong-Yong, Dar, Mohamad Aasif, Lee, Gum Hwa, Lee, Yun Il, Kim, Doyeun, Kim, Sunghoon, Kweon, Hee-Seok, Shin, Joo-Ho, Ko, Han Seok, Lee, Yunjong
• Format: Journal Article
• Language: English
• Published: United States 11.11.2020
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aax0091

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 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.