Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.683562
Title: Characterization of synapsins SUMOylation
Author: Tang, Leo Tsz-Ho
ISNI:       0000 0004 5917 1293
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2014
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Abstract:
Synapsins are neuron-specific phosphoproteins that are key components of the presynaptic neurotransmitter release machinery. Their main role is to cluster synaptic vesicles (SVs) to each other and anchor them to the actin cytoskeleton, thereby establishing the reserve vesicle pool, and then release them in response to appropriate membrane depolarisation. Here we demonstrate that, in addition to phosphorylation, SUMOylation of Synapsin la (Synla) at K687R is necessary for Synla function. SUMOylation refers to the covalent attachment of a small protein SUMO onto one of its lysine residue. The attachment of SUMO in turn causes changes in the behavior of the protein. Fluorophore-based exocytosis assay showed that replacement of endogenous Synla in neurons with a non-SUMOylatable mutant impairs stimulated SV exocytosis, primarily through a change in size of the releasable vesicle pool. Through SV binding assay and Synla dispersion assay, we found that SUMOylation enhances Synla association with SVs to promote efficient reclustering of Synla following neuronal stimulation. Co-localization assays also showed that SUMOylation aids in Synla targeting to the presynaptic terminal. Finally, the A548T mutation in Synla is strongly associated with autism spectrum disease (ASD) and epilepsy and we identify that A548T causes defective Synla SUMOylation. We further demonstrate the similar phenotype displayed by the non-SUMOylatable mutant and the A548T mutant. These results identify SUMOylation as a fundamental regulator of Synla function and reveal a novel link between reduced SUMOylation of Synla and neurological disorders.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.683562  DOI: Not available
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