| First Author | Ham S | Year | 2020 |
| Journal | Sci Transl Med | Volume | 12 |
| Issue | 569 | PubMed ID | 33177178 |
| Mgi Jnum | J:298048 | Mgi Id | MGI:6478847 |
| Doi | 10.1126/scitranslmed.aax0091 | Citation | Ham S, et al. (2020) Amyloid-like oligomerization of AIMP2 contributes to alpha-synuclein interaction and Lewy-like inclusion. Sci Transl Med 12(569) |
| abstractText | Lewy bodies are pathological protein inclusions present in the brain of patients with Parkinson's disease (PD). These inclusions consist mainly of alpha-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 alpha-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 alpha-synuclein aggregation via specific and direct binding to the alpha-synuclein monomer. The coexpression of AIMP2 and alpha-synuclein in cell cultures and in vivo resulted in the rapid formation of alpha-synuclein aggregates with a corresponding increase in toxicity. Moreover, accumulated AIMP2 in mouse brain was largely redistributed to insoluble fractions, correlating with the alpha-synuclein pathology. Last, we found that alpha-synuclein preformed fibril (PFF) seeding, adult Parkin deletion, or oxidative stress triggered a redistribution of both AIMP2 and alpha-synuclein into insoluble fraction in cells and in vivo. Supporting the pathogenic role of AIMP2, AIMP2 knockdown ameliorated the alpha-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 alpha-synuclein in mice. Because AIMP2 insolubility and coaggregation with alpha-synuclein have been seen in the PD Lewy body, targeting pathologic AIMP2 aggregation might be useful as a therapeutic strategy for neurodegenerative alpha-synucleinopathies. |
