Lewy body-associated proteins: victims, instigators, or innocent bystanders? The case of AIMP2 and alpha-synuclein

Lewy bodies (LBs), one of the neuropathological defining hallmarks of Parkinson's disease (PD), are composed of a complex mixture of alpha-synuclein (aSyn) filaments and hundreds of proteins, lipids, and membranous organelles. However, these proteins' role in aSyn aggregation and the biogenesis of LBs remains poorly understood. Previous studies have focused on investigating the role of these proteins as modifiers of aSyn aggregation, inclusion formation, and toxicity; very often, one protein at a time. In a recent study, Ham et al. suggest that one of these proteins, aminoacyl tRNA synthase complex-interacting multifunctional protein 2 (AIMP2), plays a primary role in the initiation of aSyn aggregation and is essential for aSyn inclusion formation and toxicity in cells and several models of synucleinopathies (Ham et al., 2020). Based on in vitro aggregation studies, they proposed a model in which AIMP2 self-associates to form amyloid-like aggregates that interact with monomeric aSyn and catalyze/seed the formation of aSyn fibrils and, eventually, LB-like inclusions. Herein, we present a critical analysis of their results and conclusions, review previous studies on AIMP2 aggregation, and reexamine the role of AIMP2 in regulating aSyn inclusion formation and clearance and aSyn-induced neurodegeneration in Parkinson's disease. We conclude by presenting lesson learned and recommendations on experimental factors and approaches that should be considered in future studies aimed at investigating the potential of targeting LBs-associated proteins, including AIMP2, for developing therapies to treat PD and other synucleinopathies.