Identification of PP2A and S6 Kinase as Modifiers of Leucine-Rich Repeat Kinase-Induced Neurotoxicity

• Published in: Neuromolecular medicine Vol. 22; no. 2; pp. 218 - 226
• Main Authors: Sim, Joan Poh Ling, Ziyin, Wang, Basil, Adeline Henry, Lin, Shuping, Chen, Zhongcan, Zhang, Chengwu, Zeng, Li, Cai, Yu, Lim, Kah-Leong
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.06.2020; Springer Nature B.V
• Subjects: Basal ganglia; Biomedical and Life Sciences; Biomedicine; Brain diseases; Central nervous system diseases; Drosophila; Insects; Internal Medicine; Kinases; Leucine; LRRK2 protein; Movement disorders; Mutation; Neurology; Neurosciences; Neurotoxicity; Original Paper; Parkinson's disease; Phenotypes; Phosphatase; Phosphorylation; Ribosomal protein S6 kinase; RNA-mediated interference; Neuroprotection; Mitochondria; LRRK2; Drosophila; Parkinson’s disease
• ISSN: 1535-1084; 1559-1174
• DOI: 10.1007/s12017-019-08577-z

Mutations in LRRK2 are currently recognized as the most common monogenetic cause of Parkinsonism. The elevation of kinase activity of LRRK2 that frequently accompanies its mutations is widely thought to contribute to its toxicity. Accordingly, many groups have developed LRRK2-specific kinase inhibitors as a potential therapeutic strategy. Given that protein phosphorylation is a reversible event, we sought to elucidate the phosphatase(s) that can reverse LRRK2-mediated phosphorylation, with the view that targeting this phosphatase(s) may similarly be beneficial. Using an unbiased RNAi phosphatase screen conducted in a Drosophila LRRK2 model, we identified PP2A as a genetic modulator of LRRK2-induced neurotoxicity. Further, we also identified ribosomal S6 kinase (S6K), a target of PP2A, as a novel regulator of LRRK2 function. Finally, we showed that modulation of PP2A or S6K activities ameliorates LRRK2-associated disease phenotype in Drosophila .