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UbiGABA

The role of ubiquitination in stability and plasticity of the GABAergic synapse

Total Cost €

0

EC-Contrib. €

0

Partnership

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 UbiGABA project word cloud

Explore the words cloud of the UbiGABA project. It provides you a very rough idea of what is the project "UbiGABA" about.

turnover    psychiatric    diffusion    proper    neuroligin    gabaars    excitability    functioning    ubiquitination    ubiquitinated    strength    ischemia    synapse    poly    synaptic    disorders    trafficking    molecules    molecular    either    balance    nl2    mono    excitatory    preliminary    otud4    scaffold    postsynaptic    degradation    healthy    lateral    altered    mechanism    biological    receptors    play    pathological    scaffolding    stabilised    excitotoxicity    receptor    biochemical    neurological    roles    regulates    membrane    proteasomal    gabaa    kittler    potentially    re    underlying    endocytic    cell    regulate    directing    gabaar    followed    nedd4    enzyme    intracellular    clusters    downregulation    implicated    adhesion    protein    turn    ubiquitin    epilepsy    maintained    inhibitory    gabaergic    plasticity    suggests    neurotransmitter    recruited    de    insertion    imaging    ligase    stability    lab    altering    brain    regulated    unclear    synapses    mechanisms    hetero    regulating    unk    dynamics    pentameric    gephyrin    ubiquitinating    size    neuronal    plays    poorly    regulation   

Project "UbiGABA" data sheet

The following table provides information about the project.

Coordinator
UNIVERSITY COLLEGE LONDON 

Organization address
address: GOWER STREET
city: LONDON
postcode: WC1E 6BT
website: n.a.

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country United Kingdom [UK]
 Project website http://iris.ucl.ac.uk/iris/browse/profile
 Total cost 183˙454 €
 EC max contribution 183˙454 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2014
 Funding Scheme MSCA-IF-EF-ST
 Starting year 2015
 Duration (year-month-day) from 2015-05-01   to  2017-04-30

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    UNIVERSITY COLLEGE LONDON UK (LONDON) coordinator 183˙454.00

Map

 Project objective

Proper brain functioning requires a balance between inhibitory and excitatory synaptic activity. This balance can be maintained by regulating the number of neurotransmitter receptors in the postsynaptic membrane. A major inhibitory synaptic receptor is the hetero-pentameric GABAA Receptor (GABAAR), which is stabilised in the synapse by the intracellular scaffolding protein gephyrin. Gephyrin, in turn, is recruited to and stabilised at the synapse by the adhesion protein neuroligin-2 (NL2). Regulation of synaptic strength involves lateral diffusion of GABAARs into and out of synapses, endocytic downregulation followed by either degradation or membrane re-insertion, and altering the size of gephyrin clusters. Altered GABAAR trafficking is implicated in neurological and psychiatric disorders, including epilepsy and excitotoxicity in ischemia. The underlying mechanisms, however, remain poorly understood. Ubiquitination is a well-known mechanism that regulates protein trafficking and turnover, however its role in stability and plasticity of the GABAergic synapse remains unclear. Preliminary work from the Kittler lab suggests that: 1) the ubiquitin ligase Unk plays a key role in ubiquitination of the GABAAR; 2) gephyrin can be poly-ubiquitinated and that its proteasomal turnover may be regulated by the de-ubiquitinating enzyme OTUD4; 3) NL2 can be mono-ubiquitinated, potentially directing its trafficking, and that the ubiquitin ligase Nedd4 may regulate this process. Thus ubiquitination may play several key roles in regulating the dynamics of receptor, scaffold, and adhesion molecules at the inhibitory synapse. Using molecular, biochemical, cell biological, and state-of-the-art imaging approaches I aim to study how ubiquitination of GABAARs, NL2 and gephyrin affects GABAAR trafficking, and formation and stability of the inhibitory synapse. This may lead to improved understanding of how ubiquitination regulates neuronal excitability in healthy and pathological conditions.

 Publications

year authors and title journal last update
List of publications.
2017 Hrvoje Augustin, Kieran McGourty, Joern R. Steinert, Helena M. Cochemé, Jennifer Adcott, Melissa Cabecinha, Alec Vincent, Els F. Halff, Josef T. Kittler, Emmanuel Boucrot, Linda Partridge
Myostatin-like proteins regulate synaptic function and neuronal morphology
published pages: dev.152975, ISSN: 0950-1991, DOI: 10.1242/dev.152975
Development 2019-07-24

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