Molecular Insights into the Roles of Rab Proteins in Intracellular Dynamics and Neurodegenerative Diseases
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.
KeywordsMembrane anchoring Rab proteins Molecular switches Synaptic vesicles Exocytosis Neurodegeneration
Amyloid beta protein
Amyloid precursor proteins
Adaptor protein phosphotyrosine interacting with PH domain and leucine zipper
Brain-derived neurotropic factor
Triplet nucleotide codes for glutamine
Differentially expressed in normal and neoplastic cells
Early endosome adapter1
GTP hydrolysis activator protein
Guanine nucleotide exchange factor
Lewy body disease
Leucine-rich repeat kinase 2
Mutant Huntingtin protein
Medium spiny neurons
N-acetyl d-aspartate receptor
Rab-interacting protein GDP-dissociation inhibitor
Rab escort protein
Retinal pigment epithelium
Ras genes from rat brain
Rab3A effector Rabphilin-3A
Substantia nigra pars compacta
Transmembrane protein 230
Target-soluble NSF attachment protein receptor
Vesicle associated membrane protein
Vesicle-soluble NSF attachment protein receptor
S.V. acknowledges the support of Dr. A. Ajayaghosh, Director, CSIR-NIIST, during the preparation of this manuscript. Ms. Swapna U Sasi is acknowledged for help on initial version of the manuscript.
S.V. conceived the review and the figures. P.M. contributed on neurodegenerative diseases and edited the manuscript. P.P. contributed the neurotransmitter receptors part and edited the manuscript. G.L.D. helped edit the later drafts of the manuscripts.
S.V. and P.P. acknowledge Department of Biotechnology, Ministry of Science and Technology, Government of India for financial supports as DBT-Ramalingaswami Re-entry Fellows: S.V.: SAN No.102/IFD/SAN/351/2016-14 dated May 5, 2016; and P.P: No. BT/RLF/Re-entry/04/2012. PP is also supported by DBT grant No. BT/PR10968/MED/30/1326/2014.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no competing interests.
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