LRRK2 and Parkinson's disease: from genetics to targeted therapy

Abstract

LRRK2 variants are implicated in both familial and sporadic PD. LRRK2-PD has a generally benign clinical presentation and variable pathology, with inconsistent presence of Lewy bodies and marked Alzheimer's disease pathology. The mechanisms underlying LRRK2-PD are still unclear, but inflammation, vesicle trafficking, lysosomal homeostasis, and ciliogenesis have been suggested, among others. As novel therapies targeting LRRK2 are under development, understanding the role and function of LRRK2 in PD is becoming increasingly important. Here, we outline the epidemiological, pathophysiological, and clinical features of LRRK2-PD, and discuss the arising therapeutic approaches targeting LRRK2 and possible future directions for research.

Figure 1

Schematic representation of LRRK2 gene and LRRK2 protein with its functional domains. LRRK2 pathogenic variants are indicated in red, risk variants in light blue, the protective haplotype in green. aa, amino acids; ANK, ankyrin repeat region; ARM, armadillo repeat region; Bp, base pairs; COR, C‐terminal‐of‐Roc domain; Kinase, protein tyrosine kinase‐like domain; LRR, leucine‐rich repeats; ROC, ras‐of‐complex GTPase domain; WD40, WD40 repeat region.

Figure 2

Principal mechanisms where LRRK2 has been implicated in Parkinson's disease and therapeutic targets. ASO, antisense oligonucleotides; CMA, chaperon‐mediated autophagy; M6P, mannose‐6‐phosphate, deputed to transfer of lysosomal enzymes from the Golgi to the lysosome. Created with Biorender.