Ham S, Yun SP, Kim H, Kim D, Seo BA, Kim H, Shin JY, Dar MA, Lee GH, Lee YI, Kim D, Kim S, Kweon HS, Shin JH, Ko HS, Lee Y

Lewy bodies are pathological protein inclusions present in the brain of patients with Parkinson's disease (PD). These inclusions consist mainly of ?-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, ...

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its roles in ?-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 ?-synuclein aggregation via specific and direct binding to the ?-synuclein monomer. The coexpression of AIMP2 and ?-synuclein in cell cultures and in vivo resulted in the rapid formation of ?-synuclein aggregates with a corresponding increase in toxicity. Moreover, accumulated AIMP2 in mouse brain was largely redistributed to insoluble fractions, correlating with the ?-synuclein pathology. Last, we found that ?-synuclein preformed fibril (PFF) seeding, adult Parkin deletion, or oxidative stress triggered a redistribution of both AIMP2 and ?-synuclein into insoluble fraction in cells and in vivo. Supporting the pathogenic role of AIMP2, AIMP2 knockdown ameliorated the ?-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 ?-synuclein in mice. Because AIMP2 insolubility and coaggregation with ?-synuclein have been seen in the PD Lewy body, targeting pathologic AIMP2 aggregation might be useful as a therapeutic strategy for neurodegenerative ?-synucleinopathies.

Date: Dec. 11, 2019

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