An Update on the Interplay between LRRK2, Rab GTPases and Parkinson's Disease

Abstract

Over the last decades, research on the pathobiology of neurodegenerative diseases has greatly evolved, revealing potential targets and mechanisms linked to their pathogenesis. Parkinson's disease (PD) is no exception, and recent studies point to the involvement of endolysosomal defects in PD. The endolysosomal system, which tightly controls a flow of endocytosed vesicles targeted either for degradation or recycling, is regulated by a number of Rab GTPases. Their associations with leucine-rich repeat kinase 2 (LRRK2), a major causative and risk protein of PD, has also been one of the hot topics in the field. Understanding their interactions and functions is critical for unraveling their contribution to PD pathogenesis. In this review, we summarize recent studies on LRRK2 and Rab GTPases and attempt to provide more insight into the interaction of LRRK2 with each Rab and its relationship to PD.

Keywords: LRRK2; Parkinson’s disease; Rab; endolysosome; intracellular transport.

Figure 1

Structures of LRRK2 and PD-associated mutations. (A) Primary structure of LRRK2 and the location of reported PD-associated mutations. ROC: Ras of complex domain, COR: C terminal of ROC domain, WD40: WD40 domain. Domain lengths and borders are based on [39]. (B) Monomeric structure of full-length LRRK2 [30] (PDB ID: 7HLT). (C) Homodimeric structure of full-length LRRK2 [30] (PDB ID: 7HLW). (D) Protomer of filamentous LRRK2 C-terminal half (RCKW) on microtubules [40] (PDB ID: 6VNO). All structures are aligned so that the WD40 domain lies at the top left. Colorization of structures is the same for (A–D).

Figure 2

Localizations and functions of LRRK2-phosphorylated Rabs. Green circles with numbers indicate Rabs phosphorylated by LRRK2. LRRK2-phosphorylated Rab12 and Rab29 are recruited to damaged or stressed lysosomes and further activate LRRK2. LRRK2-phosphorylated Rab8 and Rab10, bound to their effector RILPL1, accumulate near centrosomes to inhibit ciliogenesis. Rab8 and Rab10 also act together with their effector EHBP1 or EHBP1L1 to counteract lysosomal inflation or facilitate lysosomal release. LRRK2-phosphorylated Rab10 and Rab35 bind to JIP4 and induce LYTL. LRRK2-phosphorylated Rab12 binds to RILPL1 and moves lysosomes to the perinuclear region. LRRK2-phosphorylated Rab29 alters the morphology of the trans-Golgi. L: Lysosomes. Figure created with BioRender.com.