ORCID Profile
0000-0002-5397-3864
Current Organisation
The University of Edinburgh
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Publisher: Springer Science and Business Media LLC
Date: 08-06-2008
DOI: 10.1038/NN.2135
Publisher: Cold Spring Harbor Laboratory
Date: 16-08-2012
Abstract: mRNA translation, or protein synthesis, is a major component of the transformation of the genetic code into any cellular activity. This complicated, multistep process is ided into three phases: initiation, elongation, and termination. Initiation is the step at which the ribosome is recruited to the mRNA, and is regarded as the major rate-limiting step in translation, while elongation consists of the elongation of the polypeptide chain both steps are frequent targets for regulation, which is defined as a change in the rate of translation of an mRNA per unit time. In the normal brain, control of translation is a key mechanism for regulation of memory and synaptic plasticity consolidation, i.e., the off-line processing of acquired information. These regulation processes may differ between different brain structures or neuronal populations. Moreover, dysregulation of translation leads to pathological brain function such as memory impairment. Both normal and abnormal function of the translation machinery is believed to lead to translational up-regulation or down-regulation of a subset of mRNAs. However, the identification of these newly synthesized proteins and determination of the rates of protein synthesis or degradation taking place in different neuronal types and compartments at different time points in the brain demand new proteomic methods and system biology approaches. Here, we discuss in detail the relationship between translation regulation and memory or synaptic plasticity consolidation while focusing on a model of cortical-dependent taste learning task and hippoc al-dependent plasticity. In addition, we describe a novel systems biology perspective to better describe consolidation.
Publisher: EMBO
Date: 2006
DOI: 10.1038/MSB4100041
Publisher: Oxford University Press (OUP)
Date: 15-10-2005
DOI: 10.1093/HMG/DDI330
Abstract: Proteomic experiments have produced a draft profile of the overall molecular composition of the mammalian neuronal synapse. It appears that synapses have over 1000 protein components and the mapping of their interactions, organization and functions will lead to a global view of the role of synapses in physiology and disease. A major functional subcomponent of the synaptic machinery is a multiprotein complex of glutamate receptors and adhesion proteins with associated adaptor and signalling enzymes totally 185 proteins known as the N-methyl-d-aspartate receptor complex/MAGUK associated signalling complex (NRC/MASC). Here, we review the proteomic studies and functions of NRC/MASC and specifically report on the role of its component genes in human diseases. Using a systematic literature search protocol, we identified reports of mutations or polymorphisms in 47 genes associated with 183 disorders, of which 54 were nervous system disorders. A similar number of genes are important in mouse synaptic plasticity and behaviour, where the NRC/MASC acts as a signalling complex with multiple functions provided by its in idual protein components and their interactions. The in idual gene mutations suggest not only an important role for the NRC/MASC in human diseases but that these diseases may be functionally connected by their common link to the NRC/MASC. The NRC/MASC is a rich source of genetic variation and provides a platform for understanding relationships of disease phenotype amenable to systematic studies such as the Genes to Cognition research consortium (www.genes2cognition.org) that links human and mouse genetics with proteomic studies.
Publisher: Oxford University Press (OUP)
Date: 10-11-2012
DOI: 10.1093/NAR/GKS1040
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.JNEUMETH.2019.04.005
Abstract: Neurotrauma patients face major neurological sequelae. The failure in the preclinical-to-clinical translation of candidate therapies could be due to poor evaluation of rodent behaviours after neurotrauma. A home cage automated system was used to study the long term behaviour of in idual rats with traumatic brain injury (TBI), spinal cord injury (SCI) and non-CNS injured controls, whilst group-housed in their home cages. Naïve rats were used as baseline controls. Automated locomotor activity and body temperature recordings were carried out 24 h /day for 3 days/week during 12 weeks post-injury. Behavioural patterns, including aggression, rearing, grooming, feeding and drinking were analysed from automated video recordings during week 1, 6 and 12. SCI animals showed a lower locomotor activity compared to TBI or control animals during light and dark phases. TBI animals showed a higher aggression during the dark phase in the first week post-injury compared to SCI or control animals. In idual grooming and rearing were reduced in SCI animals compared to TBI and control animals in the first week post-injury during the dark phase. No differences in drinking or feeding were detected between groups. Locomotor activity did not differ between naïve male and female rats, but body temperature differ between light and dark phases for both. Injury severity was compared to standard SCI and TBI behaviour scores (BBB and mNSS, respectively) and histological analysis. This study demonstrates the practical benefits of using a non-intrusive automated home cage recording system to observe long term in idual behaviour of group-housed SCI and TBI rats.
Publisher: EMBO
Date: 2009
DOI: 10.1038/MSB.2009.27
Publisher: MDPI AG
Date: 08-2018
Abstract: The proteome of the postsynaptic terminal of excitatory synapses comprises over one thousand proteins in vertebrate species and plays a central role in behavior and brain disease. The brain is organized into anatomically distinct regions and whether the synapse proteome differs across these regions is poorly understood. Postsynaptic proteomes were isolated from seven forebrain and hindbrain regions in mice and their composition determined using proteomic mass spectrometry. Seventy-four percent of proteins showed differential expression and each region displayed a unique compositional signature. These signatures correlated with the anatomical isions of the brain and their embryological origins. Biochemical pathways controlling plasticity and disease, protein interaction networks and in idual proteins involved with cognition all showed differential regional expression. Combining proteomic and connectomic data shows that interconnected regions have specific proteome signatures. Diversity in synapse proteome composition is key feature of mouse and human brain structure.
Publisher: Public Library of Science (PLoS)
Date: 29-04-2011
Publisher: Elsevier BV
Date: 10-2017
Publisher: Society for Neuroscience
Date: 18-02-2015
DOI: 10.1523/JNEUROSCI.2866-14.2015
Abstract: The rapid regulation of cell signaling in response to calcium in neurons is essential for real-time processing of large amounts of information in the brain. A vital regulatory component, and one of the most energy-intensive biochemical processes in cells, is the elongation phase of mRNA translation, which is controlled by the Ca 2+ /CaM-dependent elongation factor 2 kinase (eEF2K). However, little is known about the dynamics of eEF2K regulation in neurons despite its established role in learning and synaptic plasticity. To explore eEF2K dynamics in depth, we stimulated synaptic activity in mouse primary cortical neurons. We find that synaptic activity results in a rapid, but transient, increase in eEF2K activity that is regulated by a combination of AMPA and NMDA-type glutamate receptors and the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) pathways. We then used computational modeling to test the hypothesis that considering Ca 2+ -coordinated MEK/ERK, mTORC1, and eEF2k activation is sufficient to describe the observed eEF2K dynamics. Although such a model could partially fit the empirical findings, it also suggested that a crucial positive regulator of eEF2K was also necessary. Through additional modeling and empirical evidence, we demonstrate that AMP kinase (AMPK) is also an important regulator of synaptic activity-driven eEF2K dynamics in neurons. Our combined modeling and experimental findings provide the first evidence that it is necessary to consider the combined interactions of Ca 2+ with MEK/ERK, mTORC1, and AMPK to adequately explain eEF2K regulation in neurons.
Publisher: Oxford University Press (OUP)
Date: 2009
DOI: 10.1093/NAR/GKN700
Publisher: Wiley
Date: 25-08-2006
Abstract: Modern high throughput technologies in biological science often create lists of interesting molecules. The challenge is to reconstruct a descriptive model from these lists that reflects the underlying biological processes as accurately as possible. Once we have such a model or network, what can we learn from it? Specifically, given that we are interested in some biological process associated with the model, what new properties can we predict and subsequently test? Here, we describe, at an introductory level, a range of bioinformatics techniques that can be systematically applied to proteomic datasets. When combined, these methods give us a global overview of the network and the properties of the proteins and their interactions. These properties can then be used to predict functional pathways within the network and to examine substructure. To illustrate the application of these methods, we draw upon our own work concerning a complex of 186 proteins found in neuronal synapses in mammals. The techniques discussed are generally applicable and could be used to examine lists of proteins involved with the biological response to electric or magnetic fields.
Publisher: Oxford University Press (OUP)
Date: 23-02-2006
DOI: 10.1093/BFGP/ELL013
Abstract: Proteomic study of the synapse has generated an extensive list of molecular components, revealing one of the most complex functional systems currently known to cell biology. While fundamental to neural information processing, behaviour and disease, the molecular organisation of the synapse and its relation to higher-level function has yet to be clearly understood. Neurotransmitter receptor complexes, such as the N-methyl-D-aspartate receptor complex (NRC/MASC), are major components of the synaptic proteome. We have recently completed a detailed study of MASC, its functional organisation and involvement in behaviour and disease. This pointed to simple design principles underlying synaptic organisation. Drawing together the results of proteomic and analytical study, we sketch out a model for synaptic functional organisation.
Publisher: Springer Science and Business Media LLC
Date: 04-12-2017
DOI: 10.1038/S41593-017-0025-9
Abstract: The postsynaptic proteome of excitatory synapses comprises ~1,000 highly conserved proteins that control the behavioral repertoire, and mutations disrupting their function cause >130 brain diseases. Here, we document the composition of postsynaptic proteomes in human neocortical regions and integrate it with genetic, functional and structural magnetic resonance imaging, positron emission tomography imaging, and behavioral data. Neocortical regions show signatures of expression of in idual proteins, protein complexes, biochemical and metabolic pathways. We characterized the compositional signatures in brain regions involved with language, emotion and memory functions. Integrating large-scale GWAS with regional proteome data identifies the same cortical region for smoking behavior as found with fMRI data. The neocortical postsynaptic proteome data resource can be used to link genetics to brain imaging and behavior, and to study the role of postsynaptic proteins in localization of brain functions.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Douglas Armstrong.