The where, what, and when of membrane protein degradation in neurons

Abstract

Membrane protein turnover and degradation are required for the function and health of all cells. Neurons may live for the entire lifetime of an organism and are highly polarized cells with spatially segregated axonal and dendritic compartments. Both longevity and morphological complexity represent challenges for regulated membrane protein degradation. To investigate how neurons cope with these challenges, an increasing number of recent studies investigated local, cargo‐specific protein sorting, and degradation at axon terminals and in dendritic processes. In this review, we explore the current answers to the ensuing questions of where, what, and when membrane proteins are degraded in neurons. © 2017 The Authors Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 78: 283–297, 2018

The Endolysosomal System and Proteostasis: From Development to Degeneration

“…Preliminary studies support a potential role for glia in regulating neuronal autophagy (Alirezaei et al, 2008;Gan et al, 2012;Madill et al, 2017). Further, glial autophagy may have profound effects on neuronal function, connectivity, and response to stress induced by injury (Gomez-Sanchez et al, 2015;Jang et al, 2016;. Because many neurodegenerative diseases may propagate through a prion-like cell-to-cell transfer of disease-associated proteins (Cushman et al, 2010;Luk et al, 2012), it remains critical to define the precise role of endolysosomal trafficking and autophagy in both neurons and glia, particularly in response to neurotoxic stress (Davis et al, 2014;Melentijevic et al, 2017;Spiller et al, 2018).…”

“…Remarkably, a number of LOAD risk variants identified through genetic screens are of genes encoding regulators of endocytic trafficking (Bertram et al, 2007;Rogaeva et al, 2007;Harold et al, 2009;Hollingworth et al, 2011;Naj et al, 2011), including Bin1 andCD2AP (Guimas Almeida et al, 2018). Using a loss-of-function approach in primary mouse cortical neurons, it was recently reported that the regulation of trafficking of APP and BACE1 through early endosomes in axons is different from dendrites.…”

High-fat diet enhances starvation-induced hyperactivity via sensitizing hunger-sensing neurons in Drosophila

“…Notably, although it was widely accepted that membrane proteins were mainly degraded by endocytosis and then lysosome (e.g. LDLR and EGFR) (Beguinot et al, 1984), it has also been reported that certain membrane proteins can be degraded via autophagy, such as GABA and AMPA receptor subunits (Jin et al, 2018).…”

Parkinson's disease: convergence on synaptic homeostasis

“…However, recent work indicates the existence of synapse‐specific mechanisms that regulate protein turnover. These may be of particular importance in the context of neurodegenerative diseases (reviewed in Vijayan & Verstreken, ; Jin et al , ) that are often characterized by misfolded, aggregated, and dysfunctional proteins [e.g., α‐Synuclein and LRRK2‐containing Lewy bodies in Parkinson's disease (PD; Spillantini et al , ; Zhu et al , )]. Neurodegeneration is often thought to start at synaptic contact sites, as these are the first cellular compartments that appear to be affected (Cheng et al , ; Burke & O'Malley, ).…”