期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 12, 期 569, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aax0091
关键词
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资金
- National Research Foundation (NRF) - Ministry of Science, ICT, and Future Planning (MSIP) [2017M3C7A1043848]
- Korea Basic Science Institute under the RD program [C030440]
- NIH/NINDS [NS38377, NS107404, NS098006]
- National Institute of Neurological Disorders and Stroke [U24 NS072026]
- National Institute of Aging [P30 AG19610]
- Arizona Department of Health Services [211002]
- Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]
- Michael J. Fox Foundation for Parkinson's Research
- National Research Council of Science & Technology (NST), Republic of Korea [C030440] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2017M3C7A1043848] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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.
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