Pharmacological inhibition of AIMP2 aggregation attenuates α-synuclein aggregation and toxicity in Parkinson’s disease

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.