PT  - JOURNAL ARTICLE
AU  - Ham, Sangwoo
AU  - Yun, Seung Pil
AU  - Kim, Hyojung
AU  - Kim, Donghoon
AU  - Seo, Bo Am
AU  - Kim, Heejeong
AU  - Shin, Jeong-Yong
AU  - Dar, Mohamad Aasif
AU  - Lee, Gum Hwa
AU  - Lee, Yun Il
AU  - Kim, Doyeun
AU  - Kim, Sunghoon
AU  - Kweon, Hee-Seok
AU  - Shin, Joo-Ho
AU  - Ko, Han Seok
AU  - Lee, Yunjong
TI  - Amyloid-like oligomerization of AIMP2 contributes to α-synuclein interaction and Lewy-like inclusion
AID  - 10.1126/scitranslmed.aax0091
DP  - 2020 Nov 11
TA  - Science Translational Medicine
PG  - eaax0091
VI  - 12
IP  - 569
4099  - http://stm.sciencemag.org/content/12/569/eaax0091.short
4100  - http://stm.sciencemag.org/content/12/569/eaax0091.full
AB  - Parkinson’s disease (PD) is characterized by the presence of Lewy bodies (LBs), abnormal protein aggregates in the neurons. In LB, α-synuclein associates with other proteins, including parkin and its substrate aminoacyl tRNA synthetase complex–interacting multifunctional protein-2 (AIMP2). The role of AIMP2 in PD pathophysiology remains unclear. Here, Ham et al. studied the role of AIMP2 in vitro and in vivo and showed that the protein had self-aggregating properties and accelerated the formation of α-synuclein aggregates. In models of α-synucleinopathies, AIMP2 was required for the formation of α-syn aggregates. The results suggest that AIMP2 plays a critical role in LB formation and might be a potential therapeutic target for reducing α-synuclein aggregates.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.