RT Journal Article
SR Electronic
T1 RIT2 reduces LRRK2 kinase activity and protects against alpha-synuclein neuropathology
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.21.348144
DO 10.1101/2020.10.21.348144
A1 Julia Obergasteiger
A1 Anne-Marie Castonguay
A1 Giulia Frapporti
A1 Evy Lobbestael
A1 Veerle Baekelandt
A1 Andrew A. Hicks
A1 Peter P. Pramstaller
A1 Claude Gravel
A1 Corrado Corti
A1 Martin Lévesque
A1 Mattia Volta
YR 2020
UL http://biorxiv.org/content/early/2020/10/21/2020.10.21.348144.abstract
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.