The effects of proteasomal inhibition on synaptic proteostasis.
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.
The Rappaport Faculty of Medicine and Research Institute, Haifa, Israel.|Network Biology Research Laboratories, Technion - Israel Institute of Technology, Haifa, Israel.
Vicky
V
Hakim
The Rappaport Faculty of Medicine and Research Institute, Haifa, Israel.|Network Biology Research Laboratories, Technion - Israel Institute of Technology, Haifa, Israel.
Laurie D
LD
Cohen
Smoler Proteomics Center, Faculty of Biology, Technion, Haifa, Israel.
Rina
R
Zuchman
Smoler Proteomics Center, Faculty of Biology, Technion, Haifa, Israel.
Tamar
T
Ziv
The Rappaport Faculty of Medicine and Research Institute, Haifa, Israel noamz@netvision.net.il.|Network Biology Research Laboratories, Technion - Israel Institute of Technology, Haifa, Israel.
Noam E
0000-0001-9197-326X
NE
Ziv
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D017208:Rats, Wistar; D013569:Synapses / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D025801:Ubiquitin; C067713:lactacystin; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine; C078846:epoxomicin

SILAC
; proteasome; proteasome inhibitors; protein degradation; synaptic proteostasis