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 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 iPSC-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. Significance Statement Parkinson’s disease (PD) is a devastating neurodegenerative disorder marked by α-synuclein accumulation. Genome wide association studies (GWAS) have identified multiple risk genes linked to PD but their functional roles and crosstalk with α-synuclein are not completely understood. Here, we screened multiple GWAS-linked genes using an in vivo α-synuclein model of PD. We discovered that loss of αri-2 (human ARIH2), an E3 ubiquitin ligase was the strongest suppressor of dopaminergic neuron loss, and identified substrates of ARIH2 in human dopaminergic neurons which mediate this pathway. This work reveals a genetic interaction between two PD linked genes, ARIH2 and α-synuclein and provides important insights into neurodegeneration in PD.