Molecular Insights into the Roles of Rab Proteins in Intracellular Dynamics and Neurodegenerative Diseases

Abstract

In eukaryotes, the cellular functions are segregated to membrane-bound organelles. This inherently requires sorting of metabolites to membrane-limited locations. Sorting the metabolites from ribosomes to various organelles along the intracellular trafficking pathways involves several integral cellular processes, including an energy-dependent step, in which the sorting of metabolites between organelles is catalyzed by membrane-anchoring protein Rab-GTPases (Rab). They contribute to relaying the switching of the secretory proteins between hydrophobic and hydrophilic environments. The intracellular trafficking routes include exocytic and endocytic pathways. In these pathways, numerous Rab-GTPases are participating in discrete shuttling of cargoes. Long-distance trafficking of cargoes is essential for neuronal functions, and Rabs are critical for these functions, including the transport of membranes and essential proteins for the development of axons and neurites. Rabs are also the key players in exocytosis of neurotransmitters and recycling of neurotransmitter receptors. Thus, Rabs are critical for maintaining neuronal communication, as well as for normal cellular physiology. Therefore, cellular defects of Rab components involved in neural functions, which severely affect normal brain functions, can produce neurological complications, including several neurodegenerative diseases. In this review, we provide a comprehensive overview of the current understanding of the molecular signaling pathways of Rab proteins and the impact of their defects on different neurodegenerative diseases. The insights gathered into the dynamics of Rabs that are described in this review provide new avenues for developing effective treatments for neurodegenerative diseases-associated with Rab defects.

Keywords: Exocytosis; Membrane anchoring; Molecular switches; Neurodegeneration; Rab proteins; Synaptic vesicles.