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Pharmacological inhibition of AIMP2 aggregation attenuates α-synuclein aggregation and toxicity in Parkinson's disease.
- Source :
-
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2022 Dec; Vol. 156, pp. 113908. Date of Electronic Publication: 2022 Oct 22. - Publication Year :
- 2022
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Abstract
- The aggregation of aminoacyl transfer RNA synthetase complex-interacting multifunctional protein-2 (AIMP2) accelerates α-synuclein aggregation via direct interaction, leading to enhanced dopaminergic neurotoxicity in Parkinson's disease (PD). Thus, it would be beneficial to prevent AIMP2 aggregation to suppress α-synucleinopathy in PD. In this study, we screened small compounds that could inhibit the in vitro aggregation of AIMP2 using a 1909 small-compound library. The AIMP2 inhibitors (SAI-04, 06, and 08) with the most effective inhibition of AIMP2 aggregation bind to AIMP2, disaggregate the pre-formed AIMP2 aggregates, and prevented AIMP2/α-synuclein coaggregation and cytotoxicity in SH-SY5Y cells. Moreover, AIMP2 inhibitors prevented α-synuclein preformed fibril (PFF)-induced pathological AIMP2 aggregation in both mouse cortical and embryonic stem cell-derived human dopaminergic neurons, thereby blocking PFF-induced α-synuclein aggregation and neurotoxicity. Collectively, our results suggest that the use of brain-permeable AIMP2 aggregation inhibitors may serve as an effective therapeutic strategy for α-synucleinopathy in PD.<br /> (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 1950-6007
- Volume :
- 156
- Database :
- MEDLINE
- Journal :
- Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
- Publication Type :
- Academic Journal
- Accession number :
- 36283223
- Full Text :
- https://doi.org/10.1016/j.biopha.2022.113908