Fig. 3

Scheme summarizing the LRRK2 putative mechanism in ubiquitination. a LRRK2 probably exists in a basal ubiquitinated (Ub) state regulated by CHIP and HSP90 to maintain LRRK2 protein stability. LRRK2 also occurs in a phosphorylated (P) state that is bound to 14–3-3 proteins. b In the presence of kinase inhibition or pathogenic PD-related mutations, including N1437H, R1441C, Y1699C, and I2020T, protein phosphatase 1 (PP1) is recruited to LRRK2, causing dephosphorylation and loss of 14–3-3 binding. c Dephosphorylation of LRRK2 promotes the addition of ubiquitin to LRRK2 through Lys48 or Lys 63-linked polyubiquitin chains. d This leads to degradation or potentially differential signaling of LRRK2 via ubiquitin linkages. e Increasing CHIP E3 ligase activity and blocking HSP90 chaperone activity can prevent the deleterious effects of LRRK2 and enhance cell viability