Abstract
Synaptic function crucially depends on uninterrupted synthesis and degradation of synaptic proteins. While much has been learned on synaptic protein synthesis, little is known on the routes by which synaptic proteins are degraded. Here we systematically studied how inhibition of the ubiquitin‐proteasome system (UPS) affects the degradation rates of thousands of neuronal and synaptic proteins. We identified a group of proteins, including several proteins related to glutamate receptor trafficking, whose degradation rates were significantly slowed by UPS inhibition. Unexpectedly, however, degradation rates of most synaptic proteins were not significantly affected. Interestingly, many of the differential effects of UPS inhibition were readily explained by a quantitative framework that considered known metabolic turnover rates for the same proteins. In contrast to the limited effects on protein degradation, UPS inhibition profoundly and preferentially suppressed the synthesis of a large number of synaptic proteins. Our findings point to the importance of the UPS in the degradation of certain synaptic proteins, yet indicate that under basal conditions most synaptic proteins might be degraded through alternative pathways.
Highlights
Chemical synapses are sites of cell–cell contact specialized for transmitting signals between neurons and other neurons, muscles, or glands
We started by measuring proteasomal activity in extracts of cortical neurons grown in culture for 2 weeks, treated prior to extraction with lactacystin (10 lM) for 4 h using the fluorogenic substrate N-Succinyl-Leu-Leu-Val-Tyr-7amino-4-methylcoumarin (Suc-LLVY-AMC; Meng et al, 1999; Fornai et al, 2003; Kisselev et al, 2003; Kisselev & Goldberg, 2005)
By combining these data with information on metabolic turnover rates of individual proteins, we devised a simple quantitative framework that explained some of the differential effects of proteasomal inhibition on protein degradation
Summary
Chemical synapses are sites of cell–cell contact specialized for transmitting signals between neurons and other neurons, muscles, or glands. Synaptic protein homeostasis (proteostasis) presents daunting challenges from the neuron’s perspective: The number of its synaptic sites can be huge, their distance from the cell body, where most protein synthesis occurs, is often enormous, and their makeup—membranal, cytoskeletal, and vesicular proteins—is extraordinarily complex. These challenges garnered considerable attention, leading to the eventual discovery of elaborate trafficking systems (reviewed in Maeder et al, 2014) and distributed capacities for protein synthesis (reviewed in Holt & Schuman, 2013).
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