Inhibiting MARS attenuates hyperhomocysteinemia-associated neurodegeneration in Parkinson's disease

Hyperhomocysteinemia is an independent risk factor for Parkinson's disease (PD). Homocysteine (Hcy) is converted to Hcy thiolactone (HTL) in error-editing reactions catalyzed by methionine-tRNA synthetase (MARS). HTL forms isopeptide bonds with lysine residues of target proteins in a process known as N-homocysteinylation (N-Hcy), which contributes to the neurotoxicity of Hcy in PD pathogenesis. Thus, MARS may represent a potential target for controlling hyperhomocysteinemia-associated neurotoxicity. Here we tested the effect of MARS on protein N-Hcy in cultured cells, MPTP-induced mouse model of PD, and mice injected with α-synuclein PFFs. We found that the protein N-Hcy levels were increased in the brains of PD model mice. MARS knockdown ameliorates protein N-Hcy, oxidative stress, mitochondrial dysfunction, and α-synuclein aggregation in cells. MARS knockdown also alleviated dopaminergic neurodegeneration and behavioral deficits in mice injected with MPTP. In mice injected with α-synuclein fibrils, MARS knockdown attenuated α-synuclein aggregation, dopaminergic neurodegeneration, and motor impairments. These results indicate that inhibition of MARS attenuates PD-like pathology induced by hyperhomocysteinemia.