August Newsletter: Rab GTPases and Neurodegeneration

Rab GTPases, members of the Ras super-family of GTPases, express at least 60 isoforms in humans1 with 24 enriched in, or specific for, the central nervous system (CNS)2. Rab GTPases are  integral regulators of intracellular membrane trafficking, regulating the formation, maturation, transport, tethering, and fusion of vesicles in the endomembrane system3. In neurons, Rab-mediated membrane/vesicle trafficking is involved in virtually every aspect of neuron physiology, and dysfunction has been implicated in several neurodegenerative diseases2,4-7 (Fig. 1). Indeed, dysfunctional membrane trafficking is an early marker of neurodegeneration5. Here, Rab-mediated trafficking defects in Parkinson’s disease (PD) and Alzheimer’s disease (AD) are reviewed.

The cause of PD is primarily idiopathic – only a small fraction of PD cases are familial and attributable to mutations in proteins that also are involved in Rab activity and membrane trafficking. Mutant proteins include Rab39b, α-synuclein, PTEN-induced putative kinase (PINK1), and leucine-rich repeat kinase 2 (LRRK2)4,6,7. Rab39b is particularly interesting because loss-of-function mutations in this gene are directly linked to inherited early-onset PD with Lewy body pathology and also...

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