The neurobiology of LRRK2 and its role in the pathogenesis of Parkinson's disease.

Leucine-rich repeat kinase 2 (LRRK2) is a large, widely expressed protein of largely unknown function. Mutations in the gene encoding LRRK2 have been linked to multiple diseases, including a prominent association with familial and sporadic Parkinson's disease (PD), as well as inflammatory bowel disorders such as Crohn's disease. The LRRK2 protein possesses both kinase and GTPase signaling domains, as well as multiple protein interaction domains. Experimental studies in both cellular and in vivo models of mutant LRRK2-induced neurodegeneration have given clues to potential function(s) of LRRK2, yet much remains unknown. For example, while it is known that intact kinase and GTPase activity are required for mutant forms of the protein to trigger cell death, the specific targets of these enzymatic activities that mediate the death of neurons are not known. In this review, we discuss the evidence linking LRRK2 to various cellular/neuronal activities such as extrinsic death and inflammatory signaling, lysosomal protein degradation, the cytoskeletal system and neurite outgrowth, vesicle trafficking, mitochondrial dysfunction, as well as multiple points of interaction with several other genes linked to the pathogenesis of PD. In order for more effective therapeutic strategies to be envisioned and implemented, the mechanisms underlying LRRK2-mediated neurodegeneration need to be better characterized. Furthermore, insights into LRRK2-associated PD pathogenesis can potentially advance our understanding of the more common sporadic forms of PD.