, ), more recent in vitro studies have reported half-lives of synaptic proteins in the range of several hours (e.g. Whereas older studies based on radiolabeling methods indicated that the half-lives of some presynaptic proteins can be remarkably long (e.g.
As a result, the estimates for such kinetics vary widely. Surprisingly, perhaps, the turnover kinetics of synaptic proteins have not yet been studied systematically. These demands in turn, depend on anabolic and catabolic rates of synaptic proteins. Given the huge numbers of synaptic connections each central nervous system neuron makes, maintenance of synaptic contents would conceivably place enormous metabolic demands on individual neurons. Proteins, including synaptic ones, have finite lifetimes and therefore, need to be continuously replaced with freshly synthesized copies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist.Ĭhemical synapses contain multitudes of proteins, some of which play direct roles in synaptic transmission, whereas others regulate synaptic function or serve as structural scaffolds. HEALTH-F2–2009–241498 (“EUROSPIN”), and the Deutsch-Israelische-Projektkooperation German-Israeli Project Cooperation foundation. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: This work has received funding from the United States Israel Binational Science Foundation (2007425), the European Union Seventh Framework Programme under grant agreement nos. Received: MaAccepted: MaPublished: May 2, 2013Ĭopyright: © 2013 Cohen et al. PLoS ONE 8(5):Įditor: Mohammed Akaaboune, University of Michigan, United States of America (2013) Metabolic Turnover of Synaptic Proteins: Kinetics, Interdependencies and Implications for Synaptic Maintenance. The relatively low turnover rates measured here (∼0.7% of synaptic protein content per hour) are in good agreement with imaging-based studies of synaptic protein trafficking, yet indicate that the metabolic load synaptic protein turnover places on individual neurons is very substantial.Ĭitation: Cohen LD, Zuchman R, Sorokina O, Müller A, Dieterich DC, Armstrong JD, et al. Some functionally or structurally related proteins exhibited very similar turnover rates, indicating that their biogenesis and degradation might be coupled, a possibility further supported by bioinformatics-based analyses. Unexpectedly, metabolic turnover rates were not significantly different for presynaptic and postsynaptic proteins, or for proteins for which mRNAs are consistently found in dendrites. We found that nearly all synaptic proteins identified here exhibited half-lifetimes in the range of 2–5 days. In the current study we used dynamic Stable Isotope Labeling with Amino acids in Cell culture (SILAC), mass spectrometry (MS), Fluorescent Non–Canonical Amino acid Tagging (FUNCAT), quantitative immunohistochemistry and bioinformatics to systematically measure the metabolic half-lives of hundreds of synaptic proteins, examine how these depend on their pre/postsynaptic affiliation or their association with particular molecular complexes, and assess the metabolic load of synaptic proteostasis. To date, the turnover kinetics of synaptic proteins have not been studied or analyzed systematically, and thus metabolic demands or the aforementioned relationships remain largely unknown. Moreover, synaptic proteostasis might differ according to distance from global protein synthesis sites, the availability of distributed protein synthesis facilities, trafficking rates and synaptic protein dynamics. Given the huge numbers of synaptic connections typical neurons form, the demand to maintain the protein contents of these connections might be expected to place considerable metabolic demands on each neuron. Chemical synapses contain multitudes of proteins, which in common with all proteins, have finite lifetimes and therefore need to be continuously replaced.
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