Activity-dependent Protein Dynamics Define Interconnected Cores of Co-regulated Postsynaptic Proteins

University of California, United States
Molecular & Cellular Proteomics (Impact Factor: 6.56). 10/2012; 12(1). DOI: 10.1074/mcp.M112.019976
Source: PubMed


Synapses are highly dynamic structures that mediate cell-cell communication in the central nervous system. Their molecular composition is altered in an activity dependent fashion, which modulates the efficacy of subsequent synaptic transmission events. While activity-dependent trafficking of individual key synaptic proteins into and out of the synapse has been characterized previously, global activity-dependent changes in the synaptic proteome have not been studied. To test the feasibility of carrying out an unbiased large scale approach we investigated alterations in the molecular composition of synaptic spines following mass-stimulation of the central nervous system induced by pilocarpine. We observe widespread changes in relative synaptic abundances encompassing essentially all proteins, supporting the view that molecular composition of the PSD is tightly regulated. In most cases, we observe that members of gene families displayed coordinate regulation even when they were not known to physically interact. Analysis of correlated synaptic localization revealed a tightly co-regulated cluster of proteins, consisting of mainly glutamate receptors and their adaptors. This cluster constitutes a functional core of the postsynaptic machinery and changes in its amount impacts on synaptic strength and size. Our data show that the unbiased investigation of activity-dependent signaling of the PSD proteome can offer valuable new information on synaptic plasticity.

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Available from: Agnes Thalhammer, Nov 26, 2015
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    • "Here, we consider some recent studies that focused on protein fractions enriched for synaptic protein components. An interesting study by Trinidad et al. (2013) reported global activity-dependent changes in the murine synaptic proteome after massive activity onset utilizing the pilocarpine model of epilepsy. They followed the regulation of more than a 100 core protein components of the postsynaptic density that were defined based on previous studies (Sheng and Hoogenraad, 2007; Fernandez et al., 2009) during the first hour after pilocarpine application, assuming that this time window covers mainly the phase of redistribution between synapse-associated and cytoplasmic protein pools. "
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    ABSTRACT: The amount and availability of proteins are regulated by their synthesis, degradation, and transport. These processes can specifically, locally, and temporally regulate a protein or a population of proteins, thus affecting numerous biological processes in health and disease states. Accordingly, malfunction in the processes of protein turnover and localization underlies different neuronal diseases. However, as early as a century ago, it was recognized that there is a specific need for normal macromolecular synthesis in a specific fragment of the learning process, memory consolidation, which takes place minutes to hours following acquisition. Memory consolidation is the process by which fragile short-term memory is converted into stable long-term memory. It is accepted today that synaptic plasticity is a cellular mechanism of learning and memory processes. Interestingly, similar molecular mechanisms subserve both memory and synaptic plasticity consolidation. In this review, we survey the current view on the connection between memory consolidation processes and proteostasis, i.e., maintaining the protein contents at the neuron and the synapse. In addition, we describe the technical obstacles and possible new methods to determine neuronal proteostasis of synaptic function and better explain the process of memory and synaptic plasticity consolidation.
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    • "We also applied hierarchical clustering, utilizing a Pearson’s correlation coefficient. Pearson’s has been shown to be a highly robust unsupervised correlation that performs well under a multitude of protein-protein interaction analyses, from identifying regulatory networks to identifying groups of proteins with shared functions [20,21]. A lack of a gold standard gene-disease-chemical network is also why no semi-supervised or supervised methods were chosen. "
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    ABSTRACT: Although respiratory diseases exhibit in a wide array of clinical manifestations, certain respiratory diseases may share related genetic mechanisms or may be influenced by similar chemical stimuli. Here we explore and infer relationships among genes, diseases, and chemicals using network and matrix based clustering methods. In order to better understand and elucidate these shared genetic mechanisms and chemical relationships we analyzed a comprehensive collection of gene, disease, and chemical relationships pertinent to respiratory disease, using network and matrix based analysis approaches. Our methods enabled us to analyze relationships and make biological inferences among over 200 different respiratory and related diseases, involving thousands of gene-chemical-disease relationships. The resulting networks provided insight into shared mechanisms of respiratory disease and in some cases suggest novel targets or repurposed drug strategies.
    Full-text · Article · Mar 2014 · BMC Systems Biology
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    • "These organized protein networks provide an efficient assembly for signal transduction and are regulated to allow strengthening and weakening of synaptic transmission. Moreover, protein constituents of the PSD are known to be dynamically influenced by synaptic activity, via mechanisms such as local translation, protein phosphorylation, ubiquitination, and degradation, as well as protein translocation into and out of synapses [9] [10]. "
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    ABSTRACT: Background: The loss of synaptic function is a pivotal mechanism in the development of Alzheimer's Disease (AD). Structural changes and loss of plasticity in the postsynaptic density (PSD) may contribute to the pathogenesis. However, the underlying molecular events triggering synaptic dysfunction remain elusive. We report a quantitative proteomic analysis of the PSD from human postmortem brain tissues of possible and definite AD cases. Methods: The analysis used both discovery and targeted mass spectrometry approaches and was repeated with biological replicates. During the discovery study, we compared several hundred proteins in the PSD-enriched fractions and found that 25 proteins were differentially regulated in AD. Results: Interestingly, the majority of these protein changes were larger in definite AD cases than in possible AD cases. In the targeted analysis, we measured the level of 9 core PSD proteins and found that only IRSp53 was highly down-regulated in AD. The alteration of selected proteins (i.e. internexin and IRSp53) was further validated by immunoblotting against 7 control and 8 AD cases. Conclusions: These results expand our understanding of how AD impacts PSD composition, and hints at new hypotheses for AD pathogenesis.
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