Back to Search
Start Over
Altered synaptobrevin-II trafficking in neurons expressing a synaptophysin mutation associated with a severe neurodevelopmental disorder.
- Source :
-
Neurobiology of disease [Neurobiol Dis] 2017 Dec; Vol. 108, pp. 298-306. Date of Electronic Publication: 2017 Sep 05. - Publication Year :
- 2017
-
Abstract
- Following exocytosis, synaptic vesicles (SVs) have to be reformed with the correct complement of proteins in the correct stoichiometry to ensure continued neurotransmission. Synaptophysin is a highly abundant, integral SV protein necessary for the efficient retrieval of the SV SNARE protein, synaptobrevin II (sybII). However the molecular mechanism underpinning synaptophysin-dependent sybII retrieval is still unclear. We recently identified a male patient with severe intellectual disability, hypotonia, epilepsy and callosal agenesis who has a point mutation in the juxtamembrane region of the fourth transmembrane domain of synaptophysin (T198I). This mutation had no effect on the activity-dependent retrieval of synaptophysin that was tagged with the genetically-encoded pH-sensitive reporter (pHluorin) in synaptophysin knockout hippocampal cultures. This suggested the mutant has no global effect on SV endocytosis, which was confirmed when retrieval of a different SV cargo (the glutamate transporter vGLUT1) was examined. However neurons expressing this T198I mutant did display impaired activity-dependent sybII retrieval, similar to that observed in synaptophysin knockout neurons. Interestingly this impairment did not result in an increased stranding of sybII at the plasma membrane. Screening of known human synaptophysin mutations revealed a similar presynaptic phenotype between T198I and a mutation found in X-linked intellectual disability. Thus this novel human synaptophysin mutation has revealed that aberrant retrieval and increased plasma membrane localisation of SV cargo can be decoupled in human disease.<br /> (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cell Membrane metabolism
Cell Membrane pathology
Cells, Cultured
Child
Developmental Disabilities genetics
Endocytosis physiology
Female
Hippocampus metabolism
Hippocampus pathology
Humans
Male
Mental Retardation, X-Linked genetics
Mental Retardation, X-Linked metabolism
Mice, Inbred C57BL
Mice, Knockout
Mutation
Neurons pathology
Synaptic Vesicles metabolism
Synaptic Vesicles pathology
Synaptophysin deficiency
Synaptophysin genetics
Biological Transport, Active physiology
Developmental Disabilities metabolism
Neurons metabolism
Vesicle-Associated Membrane Protein 2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1095-953X
- Volume :
- 108
- Database :
- MEDLINE
- Journal :
- Neurobiology of disease
- Publication Type :
- Academic Journal
- Accession number :
- 28887151
- Full Text :
- https://doi.org/10.1016/j.nbd.2017.08.021