title: SUMOylation of synapsin Ia maintains synaptic vesicle availability and is reduced in an autism mutation.
abstract: Synapsins 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 to establish the reserve vesicle pool, and then release them in response to appropriate membrane depolarization. Here we demonstrate that SUMOylation of synapsin Ia (SynIa) at K687 is necessary for SynIa function. Replacement of endogenous SynIa with a non-SUMOylatable mutant decreases the size of the releasable vesicle pool and impairs stimulated SV exocytosis. SUMOylation enhances SynIa association with SVs to promote the efficient reclustering of SynIa following neuronal stimulation and maintain its presynaptic localization. The A548T mutation in SynIa is strongly associated with autism and epilepsy and we show that it leads to defective SynIa SUMOylation. These results identify SUMOylation as a fundamental regulator of SynIa function and reveal a novel link between reduced SUMOylation of SynIa and neurological disorders.
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: Leo T-H
authors.initials: LT
authors.lastname: Tang
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Craig
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Henley
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D004827:Epilepsy / Q000235:genetics*; D005089:Exocytosis / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D058207:Sumoylation; D013569:Synapses / Q000378:metabolism; D016704:Synapsins / Q000235:genetics* / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics*; D013572:Synaptic Vesicles / Q000378:metabolism*
chemical_list: D016704:Synapsins