LRRK2: Genetic mechanisms vs genetic subtypes.

In 2004, the identification of pathogenic variants in the LRRK2 gene across several families with autosomal dominant late-onset Parkinson's disease (PD) revolutionized our understanding of the role of genetics in PD. Previous beliefs that genetics in PD was limited to rare early-onset or familial forms of the disease were quickly dispelled. Currently, we recognize LRRK2 p.G2019S as the most common genetic cause of both sporadic and familial PD, with more than 100,000 affected carriers across the globe. The frequency of LRRK2 p.G2019S is also highly variable across populations, with some regions of Asian or Latin America reporting close to 0%, contrasting to Ashkenazi Jews or North African Berbers reporting up to 13% and 40%, respectively. Patients with LRRK2 pathogenic variants are clinically and pathologically heterogeneous, highlighting the age-related variable penetrance that also characterizes LRRK2-related disease. Indeed, the majority of patients with LRRK2-related disease are characterized by a relatively mild Parkinsonism with less motor symptoms with variable presence of α-synuclein and/or tau aggregates, with pathologic pleomorphism widely described. At a functional cellular level, it is likely that pathogenic variants mediate a toxic gain-of-function of the LRRK2 protein resulting in increased kinase activity perhaps in a cell-specific manner; by contrast, some LRRK2 variants appear to be protective reducing PD risk by decreasing the kinase activity. Therefore, employing this information to define appropriate patient populations for clinical trials of targeted kinase LRRK2 inhibition strategies is very promising and demonstrates a potential future application for PD using precision medicine.