RIT2 reduces LRRK2 kinase activity and protects against alpha-synuclein neuropathology

Abstract

In Parkinson's disease (PD) misfolded alpha-synuclein (aSyn) accumulates in the substantia nigra, where dopaminergic neurons are progressively lost. The mechanisms underlying aSyn pathology are still unclear but hypothesized to involve the autophagy lysosome pathways (ALP). LRRK2 mutations are a major cause of familial and sporadic PD, hyperactivate kinase activity and its pharmacological inhibition reduces pS129-aSyn inclusions. We observed selective downregulation of the novel PD risk factor RIT2 in G2019S-LRRK2 expressing cells. Here we studied whether RIT2 could modulate LRRK2 kinase activity. RIT2 overexpression in G2019S-LRRK2 cells rescued ALP abnormalities and diminished aSyn inclusions. In vivo, viral mediated overexpression of RIT2 operated neuroprotection against AAV-A53T-aSyn. Furthermore, RIT2 overexpression prevented the A53T-aSyn-dependent increase of LRRK2 kinase activity in vivo. Our data indicate that RIT2 inhibits overactive LRRK2 to ameliorate ALP impairment and counteract aSyn aggregation and related deficits. Targeting RIT2 could represent a novel strategy to combat neuropathology in familial and idiopathic PD.

A pH-eQTL Interaction at the RIT2–SYT4 Parkinson’s Disease Risk Locus in the Substantia Nigra

“…Known molecular mechanisms that could explain the observed pH-eQTL are lacking. One exception is a recent study of interactions between RIT2 and LRRK2 (Obergasteiger et al, 2021). Using postmortem gene expression data, Obergasteiger et al observed down-regulation of RIT2 in the substantia nigra of PD cases.…”