PT  - JOURNAL ARTICLE
AU  - Julia Obergasteiger
AU  - Anne-Marie Castonguay
AU  - Giulia Frapporti
AU  - Evy Lobbestael
AU  - Veerle Baekelandt
AU  - Andrew A. Hicks
AU  - Peter P. Pramstaller
AU  - Claude Gravel
AU  - Corrado Corti
AU  - Martin Lévesque
AU  - Mattia Volta
TI  - RIT2 reduces LRRK2 kinase activity and protects against alpha-synuclein neuropathology
AID  - 10.1101/2020.10.21.348144
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.21.348144
4099  - http://biorxiv.org/content/early/2020/10/21/2020.10.21.348144.short
4100  - http://biorxiv.org/content/early/2020/10/21/2020.10.21.348144.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.