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Endocytic membrane trafficking and neurodegenerative disease

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Abstract

Neurodegenerative diseases are amongst the most devastating of human disorders. New technologies have led to a rapid increase in the identification of disease-related genes with an enhanced appreciation of the key roles played by genetics in the etiology of these disorders. Importantly, pinpointing the normal function of disease gene proteins leads to new understanding of the cellular machineries and pathways that are altered in the disease process. One such emerging pathway is membrane trafficking in the endosomal system. This key cellular process controls the localization and levels of a myriad of proteins and is thus critical for normal cell function. In this review we will focus on three neurodegenerative diseases; Parkinson disease, amyotrophic lateral sclerosis, and hereditary spastic paraplegias, for which a large number of newly discovered disease genes encode proteins that function in endosomal membrane trafficking. We will describe how alterations in these proteins affect endosomal function and speculate on the contributions of these disruptions to disease pathophysiology.

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

AP-2/AP-5:

Adaptor protein complex 2/5

CCPs:

Clathrin-coated pits

CCVs:

Clathrin-coated vesicles

CME:

Clathrin-mediated endocytosis

CHC:

Clathrin heavy chain

CLCs:

Clathrin light chains

DENN:

Differentially expressed in normal and neoplastic cells

EEA1:

Early endosome antigen 1

EGFR:

Epidermal growth factor receptor

ESCRT:

Endosomal sorting complex required for transport

GAK:

Cyclin G-associated kinase

GARP:

Golgi-associated retrograde protein

GBA:

Glucocerebrosidase

GEF:

Guanine nucleotide exchange factor

HSP:

Hereditary spastic paraplegia

ILVs:

Intralumenal vesicles

KRS:

Kufor-Rakeb syndrome

LRRK2:

Leucine-rich repeat kinase 2

MDVs:

Mitochondria-derived vesicles

MPR:

Mannose-6-phosphate receptor

MVBs:

Multivesicular bodies

OCRL:

Oculocerebrorenal syndrome of Lowe

PD:

Parkinson disease

PINK1:

PTEN-induced kinase 1

PtdIns:

Phosphatidylinositol

PtdIns(4,5)P2:

Phosphatidylinositol 4,5-bisphosphate

PtdIns(3)P:

Phosphatidylinositol 3-phosphate

PtdIns(4)P:

Phosphatidylinositol 4-phosphate

SNARE:

Soluble NSF attachment protein receptor

SNX:

Sorting nexin

STAM:

Signal transducing adaptor protein molecule

TGN:

Trans-Golgi network

UbBD:

Ubiquitin-binding domain

V-ATPase:

Vacuolar (H+)-ATPases proton pump

Vps:

Vacuolar protein sorting

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Acknowledgments

This work was supported by Grants from the Canadian Institutes of Health Research to P.S.M. A.M.A.S. was supported by a fellowship from Parkinson Society of Canada. E.A.F. is a Chercheur National of the FRQS and P.S.M. is a James McGill Professor and Fellow of the Royal Society of Canada.

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  1. Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC, H3A 2B4, Canada

    Andrea M. A. Schreij, Edward A. Fon & Peter S. McPherson

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Schreij, A.M.A., Fon, E.A. & McPherson, P.S. Endocytic membrane trafficking and neurodegenerative disease. Cell. Mol. Life Sci. 73, 1529–1545 (2016). https://doi.org/10.1007/s00018-015-2105-x

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  • DOI: https://doi.org/10.1007/s00018-015-2105-x

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