Amyloid-like oligomerization of AIMP2 contributes to α-synuclein interaction and Lewy-like inclusion.
Sangwoo HamSeung Pil YunHyo-Jung KimDonghoon KimBo Am SeoHeejeong KimJeong-Yong ShinMohamad Aasif DarGum Hwa LeeYun Il LeeDoyeun KimSunghoon KimHee-Seok KweonJoo-Ho ShinHan Seok KoByoung Dae LeePublished in: Science translational medicine (2021)
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.
Keyphrases
- cell death
- oxidative stress
- squamous cell carcinoma
- type diabetes
- parkinson disease
- stem cells
- young adults
- radiation therapy
- single cell
- neoadjuvant chemotherapy
- amino acid
- cell therapy
- spinal cord injury
- spinal cord
- signaling pathway
- adipose tissue
- dna damage
- cell proliferation
- nucleic acid
- diabetic rats
- molecularly imprinted