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.

在帕金森病 (PD) 中，错误折叠的 α-突触核蛋白 (aSyn) 在黑质中积累，多巴胺能神经元在黑质中逐渐丢失。aSyn 病理学的潜在机制仍不清楚，但假设它们涉及自噬溶酶体途径 (ALP)。LRRK2 突变是家族性和散发性 PD 的主要原因，LRRK2 激酶活性已显示参与 pS129-aSyn 包涵体调节。我们观察到新型 PD 风险因子RIT2的选择性下调体外和体内。G2019S-LRRK2 细胞中的 Rit2 过表达挽救了 ALP 异常并减少了 aSyn 包涵体。在体内，病毒介导的 Rit2 过表达对 AAV-A53T-aSyn 具有神经保护作用。此外，Rit2 过表达阻止了体内 LRRK2 激酶活性的 A53T-aSyn 依赖性增加。另一方面，Rit2 水平的降低导致 ALP 缺陷，类似于 G2019S-LRRK2 突变诱导的缺陷。我们的数据表明 Rit2 是正确的溶酶体功能所必需的，可抑制过度活跃的 LRRK2 以改善 ALP 损伤，并抵消 aSyn 聚集和相关缺陷。靶向 Rit2 可能代表一种有效的策略来对抗家族性和特发性 PD 的神经病理学。