LRRK2 and ubiquitination: implications for kinase inhibitor therapy.
Pathogenic mutations and risk variants in LRRK2 (leucine-rich repeat kinase 2) represent the most common genetic cause of familial and sporadic PD (Parkinson's disease). LRRK2 protein is widely expressed throughout the brain and the periphery. Structurally, LRRK2 contains several functional domains, including a dual enzymatic core consisting of a kinase and GTPase domain. Disease-linked variants are found in both these enzymatic domains as well as in the COR [C-terminal of ROC (Ras of complex proteins)] and WD40 protein-protein binding domain. The kinase domain is widely believed to be linked to toxicity, and thus the thrust of pharmaceutical effort has focused on developing LRRK2 kinase inhibitors. However, recent data have suggested that inhibition of LRRK2 activity results in reduced LRRK2 levels and peripheral side effects, which are similar to those observed in homozygous LRRK2-knockout and LRRK2 kinase-dead rodent models. In a recent issue of the Biochemical Journal, a study led by Nichols reveals that dephosphorylation of LRRK2 cellular phosphorylation sites (Ser(910)/Ser(935)/Ser(955)/Ser(973)) triggers its ubiquitination and subsequent degradation and thus may account for the loss of function phenotypes observed in peripheral tissues in LRRK2-knockout/kinase-dead or inhibitor-treated rodents and primates. Albeit negative from a kinase inhibitor standpoint, the data open new avenues for LRRK2 biology and therapeutic approaches to counteract LRRK2 toxicity.
Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, U.S.A. melrose.heather@mayo.edu.
Heather L
HL
Melrose
D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D003593:Cytoplasm / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
D048948:14-3-3 Proteins; D017346:Protein Serine-Threonine Kinases
GNE1023; LRRK2; Parkinson’s disease; kinase inhibitor; phosphorylation site; ubiquitin