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.
Highlights
Maintaining neurotransmission is essential for normal brain communication
The combination of problems in our patient differs from the previously reported patients, because hypogonadism, severe hypotonia and callosal agenesis have not been previously described and define a recognisable, syndromic type of X-linked intellectual disability (Tarpey et al, 2009). When this mutant was expressed in a knockout system, it did not impact on synaptophysin trafficking or synaptic vesicle (SV) endocytosis
It did have a selective effect on the activity-dependent retrieval of its interaction partner synaptobrevin II (sybII), but not on sybII targeting to nerve terminals or plasma membrane levels
Summary
Maintaining neurotransmission is essential for normal brain communication. a large body of evidence is emerging indicating that altered synaptic transmission can result in a series of neurodegenerative and neurodevelopmental disorders (Milnerwood and Raymond, 2010; Sheng et al, 2012; Zoghbi and Bear, 2012). In particular synaptic dysfunction has been increasingly associated the genesis and presentation of neurodevelopmental disorders (Wijetunge et al, 2013; Zoghbi and Bear, 2012) The majority of these studies have focused on postsynaptic dysfunction, several recent studies have highlighted presynaptic dysfunction as a potentially causal mechanism (Giovedi et al, 2014; Valente et al, 2016; Waites and Garner, 2011). Recent studies have highlighted mutations in a series of key presynaptic genes that result in altered neurotransmitter release due to either perturbations in the number of SVs available for fusion (Corradi et al, 2014; Deng et al, 2011; Fassio et al, 2011; Myrick et al, 2015), coupling of SV fusion to calcium influx (Baker et al, 2015; Ferron et al, 2014; Valente et al, 2016; Whittaker et al, 2015), or the efficiency of the SV fusion event itself (Deciphering Developmental Disorders, 2015; Saitsu et al, 2008). In addition mutations in a number of SV endocytosis genes have been linked to neurodevelopmental disorders (Deciphering Developmental Disorders, 2015; Dhindsa et al, 2015; Euro et al, 2014; Serajee and Huq, 2015) suggesting accurate SV formation is important for normal presynaptic function
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