LRRK2 and the Endolysosomal System in Parkinson's Disease

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant familial Parkinson's disease (PD), with pathogenic mutations enhancing LRRK2 kinase activity. There is a growing body of evidence indicating that LRRK2 contributes to neuronal damage and pathology both in familial and sporadic PD, making it of particular interest for understanding the molecular pathways that underlie PD. Although LRRK2 has been extensively studied to date, our understanding of the seemingly diverse functions of LRRK2 throughout the cell remains incomplete. In this review, we discuss the functions of LRRK2 within the endolysosomal pathway. Endocytosis, vesicle trafficking pathways, and lysosomal degradation are commonly disrupted in many neurodegenerative diseases, including PD. Additionally, many PD-linked gene products function in these intersecting pathways, suggesting an important role for the endolysosomal system in maintaining protein homeostasis and neuronal health in PD. LRRK2 activity can regulate synaptic vesicle endocytosis, lysosomal function, Golgi network maintenance and sorting, vesicular trafficking and autophagy, with alterations in LRRK2 kinase activity serving to disrupt or regulate these pathways depending on the distinct cell type or model system. LRRK2 is critically regulated by at least two proteins in the endolysosomal pathway, Rab29 and VPS35, which may serve as master regulators of LRRK2 kinase activity. Investigating the function and regulation of LRRK2 in the endolysosomal pathway in diverse PD models, especially in vivo models, will provide critical insight into the cellular and molecular pathophysiological mechanisms driving PD and whether LRRK2 represents a viable drug target for disease-modification in familial and sporadic PD.

Keywords: Leucine-rich repeat kinase 2; Parkinson’s disease; endocytosis; lysosomes; trans-Golgi network; vesicular trafficking.

Fig. 1

LRRK2 protein domain architecture with PD-linked familial mutations (red), sporadic PD risk variants (black), and sporadic PD protective variants (green), as indicated.

Fig. 2

LRRK2 in the endolysosomal pathway. Key aspects of the endolysosomal pathway highlighting LRRK2-interacting proteins and kinase substrates. *The specific subcellular location of VPS35-induced activation of LRRK2 and subsequent Rab10 phosphorylation not been established. As VPS35 resides in the retromer complex, and the retromer complex primarily localizes to endosomal and vesicular membranes in the retrograde trafficking pathway, it most likely occurs on endosomal membranes, however this has not been directly assessed.