In Vivo Screen of Parkinson’s Disease GWAS Risk Genes Identifies ARIH2 as a Novel Regulator of α-Synuclein Toxicity in Dopaminergic Neurons

Parkinson's disease (PD) is a late-onset neurodegenerative disease characterized by preferential degeneration of midbrain dopaminergic neurons and α-synuclein–containing Lewy bodies that are found in both familial and sporadic forms. Genome-wide association studies (GWAS) have identified many loci associated with risk of sporadic PD, but their role in PD pathogenesis remains largely unknown. We screened a subset of GWAS genes in Caenorhabditis elegans ( C. elegans ) as potential modulators of α-synuclein–mediated degeneration of dopaminergic neurons. Loss of ari-2 (human ARIH2 ), an E3 ubiquitin ligase, was identified as the strongest suppressor of dopaminergic neurodegeneration in C. elegans. Unbiased proteomics analysis in human-induced pluripotent stem cell-derived dopaminergic neurons revealed novel substrates of ARIH2 including TPPP3, a regulator of microtubule dynamics. Importantly, TPPP3 was required for ARIH2's effects on α-synuclein–induced dopaminergic neurodegeneration. Our studies reveal an unexpected genetic interaction between two PD-linked genes, α-synuclein and ARIH2 , and suggest that inhibition of ARIH2's enzymatic activity may serve as a potential therapeutic approach in PD.