The role of Rab GTPases in the pathobiology of Parkinson' disease

Abstract

Rab GTPases are key regulators of vesicle-mediated transport and are proposed to play a crucial role in the pathobiology of Parkinson's disease. As membrane trafficking seems to be a relevant pathway altered in Parkinson' disease, understanding the role of Rab GTPases in the disease progression could open a window for therapeutic interventions. In this review, we focus on the recent advances on the role of Rab GTPases in the biology of two main proteins involved in Parkinson's disease: LRRK2 and α-synuclein, given that mutations in their genes (LRRK2 and SNCA) cause familial and sporadic Parkinson's disease.

Figure 1.. The Parkinson’s disease kinase LRRK2 and its Rab substrates.

LRRK2 with its seven domains (the Kinase domain colored in red). Upon activation, LRRK2 phosphorylates its auto-phosphorylation site (S1292) and 14 different Rab GTPases (Rab3A/B/C/D, Rab5A/B/C, Rab8A/B, Rab10, Rab12, Rab29, Rab35 and Rab43). In blue, pathogenic mutations found in familial cases of late-onset autosomal dominant PD. ARM, Armadillo. ANK, Ankyrin. LRR, Leucine-rich repeat. ROC, Ras of complex. COR, C-terminal of ROC. KIN, Kinase. P, phosphorylation.

Figure 2.. LRRK2-dependent Rab GTPases cellular functions.

Schematic representation on the proposed functions of Rab GTPases that are substrates for LRRK2 (Rab8A, Rab10 and Rab29). Thin arrows indicate LRRK2-mediated phosphorylation. Phosphorylated Rab10 blocks ciliogenesis and phosphorylated Rab8A disrupts centrosome positioning. Overload late endosomes/lysosomes recruit LRRK2 that in turns phosphorylates Rab8A and Rab10. The proposed mechanism suggests a consequent recruitment of effectors EHBP1 and EHBP1L1 to promote lysosomal exocytosis. LE, late endosome. LYS, lysosome. P, phosphorylation. Question marks indicate unresolved aspects of the model.

Figure 3.. Rab GTPases as key regulators of ??-synuclein aggregation, propagation and clearance.

The cartoon depicts the role of certain Rab GTPases as important modifiers of ??-synuclein biology. MVB, multivesicular body. LE, late endosome. LYS, lysosome. P, phosphorylation. Question marks indicate unresolved aspects of the model.