Endocytic membrane trafficking and neurodegenerative disease

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.

Keywords: ALS; Alzheimer disease; Clathrin; Endocytosis; Endosome; HSP; Lysosomal storage disease; MVB; Multivesicular body; Neurodegeneration; PD; TGN; Trans-Golgi network.

Fig. 1

Various steps/organelles in endocytic membrane trafficking are diagrammed. Proteins that are encoded by genes altered in neurodegenerative diseases are indicated and are color-coded (blue PD, red ALS, green HSP)