Keeping synapses in shape: degradation pathways in the healthy and aging brain

Abstract

Synapses maintain their molecular composition, plasticity and function through the concerted action of protein synthesis and removal. The complex and polarized neuronal architecture poses specific challenges to the logistics of protein and organelle turnover since protein synthesis and degradation mainly happen in the cell soma. In addition, post-mitotic neurons accumulate damage over a lifetime, challenging neuronal degradative pathways and making them particularly susceptible to the effects of aging. This review will summarize the current knowledge on neuronal protein turnover mechanisms with a particular focus on the presynapse, including the proteasome, autophagy and the endolysosomal route and their roles in regulating presynaptic proteostasis and function. In addition, the author will discuss how physiological brain aging, which entails a progressive decline in cognitive functions, affects synapses and the degradative machinery.

Keywords: aging; autophagy; endolysosome; presynapse; proteostasis; ubiquitin proteasome system.

Figure 1. Degradative pathways and suggested presynaptic cargos

Synaptic proteins and organelles, such as SVs and mitochondria, can be locally removed via alternative degradative routes. The proteasome removes predominantly cytosolic proteins, including active zone proteins RIM1 and Munc13. ESCRT-dependent endolysosomal sorting is thought to be required for the degradation of a subset of membrane proteins, for instance, SV proteins VAMP2 and SV2. Both proteins and organelles can be sequestered by a double-membrane structure called a phagophore, which then closes to form an autophagosome that eventually fuses with somatic lysosomes for degradation. Ubiquitination is a common signal for degradation in all of these major protein degradation pathways. Therefore, ubiquitin-ligases (E3) and deubiquitinating enzymes could play important roles in maintaining a healthy presynapse. The six E3 ligases indicated here either have known, mammalian, presynaptic targets (Nedd4, Scrapper, Fbxo45, Staring) or are locally regulated by presynaptic proteins (Siah1, Parkin); EE, early endosome; SV, synaptic vesicle; MVB, multivesicular body.