LRRK2 kinase in Parkinson's disease

Despite intensive research, attempts to pause or even just slow the progression of Parkinson's disease (PD) have thus far failed. Although most cases of PD are idiopathic and with largely unknown aetiology, mutations in ∼20 genes, including LRRK2 (leucine-rich repeat kinase 2), cause rare genetic Parkinsonism. All pathogenic mutations in LRRK2 result in hyperactivation of the LRRK2 kinase, offering the prospect of elaborating disease-modifying treatments. Indeed, LRRK2 inhibitors have entered phase 1 clinical trials. Data are also emerging for LRRK2 involvement in idiopathic PD, suggesting that inhibitors may benefit patients beyond those carrying LRRK2 mutations. Recent advances point toward a role for LRRK2 in regulating autophagy, an intracellular process that delivers cytoplasmic constituents to the lysosome for degradation and recycling. LRRK2 phosphorylates a subgroup of RAB proteins and regulates their ability to bind cognate effector proteins. Additionally, LRRK2 is highly expressed in immune cells. Intriguing research indicates that, in early life, increased LRRK2 activity may protect against opportunistic pathogenic infection but then later increases the risk of developing PD, a concept called antagonistic pleiotropy.