Heterogeneity of leucine-rich repeat kinase 2 mutations: genetics, mechanisms and therapeutic implications

Abstract

Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

Fig. 1

LRRK2 domain structure, localization of mutations, and proposed pathogenic mechanisms. ARM = armadillo repeats; ANK = ankyrin repeats; ROC = Ras of complex proteins; COR = C-terminus of ROC, kinase domain, and WD40 domain; GTP

Fig. 2

Pathogenic mechanisms of LRRK2 mutations (modified from [151]). Many pathogenic mechanisms have been reported for LRRK2 mutations. Among those there is a growing number of evidence of involvement of LRRK2 in different vesicle trafficking events, including endocytosis [152, 171], Golgi clearance [43, 51, 126, 150, 151], cytoskeleton dynamics [–, , , , , , , –174], lysosomal dynamics [143], and autophagy [124, 140, 142, 146, 175]. Different pathogenic LRRK2 mutations can cause alterations of at least some of these events. Please note that lack of indication that a specific mutation has a given effect does not necessarily mean that a negative result has been reported; in most cases not all mutations have been tested