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

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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.

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Abbreviations

α-Syn:

Alpha-synuclein

AD:

Alzheimer’s disease

Aβ:

Amyloid beta protein

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

APP:

Amyloid precursor proteins

APPL:

Adaptor protein phosphotyrosine interacting with PH domain and leucine zipper

BBSome:

Bardet–Biedl syndrome

BDNF:

Brain-derived neurotropic factor

CAG:

Triplet nucleotide codes for glutamine

CCV:

Clathrin-coated vesicles

CMTB:

Charcot–Marie–Tooth-type 2B

CRD:

Cone-rod dystrophy

CR:

Carpenter syndrome

DA:

Dopamine

DENN:

Differentially expressed in normal and neoplastic cells

EE:

Early endosomes

EEA1:

Early endosome adapter1

EAAC1:

Glutamate/cysteine transporter

ER:

Endoplasmic reticulum

GAP:

GTP hydrolysis activator protein

GC:

Golgi complex

GDP:

Guanosine diphosphate

GEF:

Guanine nucleotide exchange factor

GLUT:

Glucose transporter

GTP:

Guanosine triphosphate

GS:

Griscelli syndrome

GSH:

Glutathione

HD:

Huntington’s disease

Hh:

Hedgehog

HTT:

Huntingtin protein

IFT:

Intraflagellar transport

LBD:

Lewy body disease

LE:

Late endosome

LRRK:

Leucine-rich repeat kinase 2

LTP:

Long-term potentiation

LTD:

Long-term depression

MAM:

Mitochondria-associated membranes

mHTT:

Mutant Huntingtin protein

MS:

Martsolf syndrome

MSN:

Medium spiny neurons

NMDA:

N-acetyl d-aspartate

NMDAR:

N-acetyl d-aspartate receptor

NSF:

N-ethylmaleimide-sensitive factor

PD:

Parkinson’s disease

polyQ:

Polyglutamine

PSEN-1:

Presenilin-1

Rab-GDI:

Rab-interacting protein GDP-dissociation inhibitor

REP:

Rab escort protein

RPE:

Retinal pigment epithelium

Rab:

Ras genes from rat brain

RBP3A:

Rab3A effector Rabphilin-3A

RE:

Recycling endosome

SNpc:

Substantia nigra pars compacta

SV:

Synaptic vesicle

TGN:

Trans-Golgi network

TMEM230:

Transmembrane protein 230

TrkB:

Tyrosine kinase-B

t-SNARE:

Target-soluble NSF attachment protein receptor

VAMP:

Vesicle associated membrane protein

v-SNARE:

Vesicle-soluble NSF attachment protein receptor

WMS:

Warburg-microsyndrome

Ypt:

Yeast-related protein

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Acknowledgements

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.

Funding

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.

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Authors and Affiliations

  1. Biochemistry and Molecular Mechanisms Lab, APTD, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Council of Scientific and Industrial Research (CSIR), Ministry of Science and Technology, Government of India, Industrial Estate PO, Thiruvananthapuram, Kerala, 695019, India

    Shobi Veleri

  2. Molecular Medicine, Applied Biology, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, 695012, India

    Pradeep Punnakkal

  3. Field Neurosciences Institute Laboratory for Restorative Neurology, Program in Neuroscience, Department of Psychology, Central Michigan University, Mt. Pleasant, MI, 48859, USA

    Gary L. Dunbar & Panchanan Maiti

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  1. Shobi Veleri
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  2. Pradeep Punnakkal
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  3. Gary L. Dunbar
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  4. Panchanan Maiti
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Contributions

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.

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Correspondence to Shobi Veleri.

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Veleri, S., Punnakkal, P., Dunbar, G.L. et al. Molecular Insights into the Roles of Rab Proteins in Intracellular Dynamics and Neurodegenerative Diseases. Neuromol Med 20, 18–36 (2018). https://doi.org/10.1007/s12017-018-8479-9

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