The small GTPase Rit2 modulates LRRK2 kinase activity, is required for lysosomal function 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 they are hypothesized to involve the autophagy-lysosome pathway (ALP). LRRK2 mutations are a major cause of familial and sporadic PD, and LRRK2 kinase activity has been shown to be involved in pS129-aSyn inclusion modulation. We observed selective downregulation of the novel PD risk factor RIT2 in vitro and in vivo. 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. On the other hand, reduction of Rit2 levels leads to defects in the ALP, similar to those induced by the G2019S-LRRK2 mutation. Our data indicate that Rit2 is required for correct lysosome function, inhibits overactive LRRK2 to ameliorate ALP impairment, and counteracts aSyn aggregation and related deficits. Targeting Rit2 could represent an effective strategy to combat neuropathology in familial and idiopathic PD.

Selective dopaminergic vulnerability in Parkinson’s disease: new insights into the role of DAT

“…A recent meta-analysis of genome-wide association studies (GWAS), interrogating data from >13,000 PD patients and > 95,000 controls, identified 26 genetic loci across the genome associated with PD. Intriguingly, 16 out of these 26 genetic loci have 18 genes nearby that modulate ALP, namely SYT11 ( Bento et al, 2016 ), RAB7L1 ( Kuwahara et al, 2016 ; Pradhan et al, 2018 ; Shrivastava et al, 2022 ), NUCKS1 ( Zhao et al, 2020 ), GBA ( Murphy and Halliday, 2014 ; Pang et al, 2022 ; Pradas and Martinez-Vicente, 2023 ), SIPA1L2 ( Andres-Alonso et al, 2019 ), TMEM163 ( Cuajungco et al, 2014 ; Cuajungco and Kiselyov, 2017 ), STK39 ( Gallolu Kankanamalage et al, 2016 , 2017 ; He et al, 2022 ), LAMP3 ( Tanaka et al, 2022 ), TMEM175 ( Jinn et al, 2017 ; Hu et al, 2022 ), GAK ( Miyazaki et al, 2021 ; Munson et al, 2021 ), SCARB2 ( Velayati et al, 2011 ), GPNMB ( Robinet et al, 2021 ; Zhu et al, 2022 ), VPS13C ( Cai et al, 2022 ; Hancock-Cerutti et al, 2022 ), RIT2 ( Obergasteiger et al, 2023 ), DDRGK1 ( Cao et al, 2021 ), SNCA ( Sampaio-Marques et al, 2012 ; Song et al, 2014 ), LRRK2 ( Gómez-Suaga and Hilfiker, 2012 ; Orenstein et al, 2013 ; Ysselstein et al, 2019 ), and MAPT ( Zhu et al, 2017 ; Feng et al, 2020 ).…”

Rit2 silencing in dopamine neurons drives a Parkinsonian phenotype

“…Moreover, Rit2 overexpression is sufficient to rescue cellular and behavioral deficits in an synuclein (-syn) mouse PD model 33 . Together, these findings suggest that Rit2 plays a key role in DAN function and viability, and may be a critical factor in PD pathogenesis.…”

“…Significant Rit2 mRNA decreases were reported in postmortem PD patient SNc 31 , and a recent scRNAseq study identified a major transcriptomic cluster in SNc DANs from PD subjects with striking Rit2 expression loss 32 . Moreover, Rit2 overexpression is sufficient to rescue cellular and behavioral deficits in an α- synuclein (α-syn) mouse PD model 33 . Together, these findings suggest that Rit2 plays a key role in DAN function and viability, and may be a critical factor in PD pathogenesis.…”