Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling

Baker, Kate; Gordon, Sarah; Grozeva, Detelina; Kogelenberg, Margriet van; Roberts, Nicola Y.; Pike, Michael; Blair, Edward; Hurles, Matthew E.; Chong, W.K.; Baldeweg, Torsten; Kurian, Manju A.; Boyd, Stewart; Cousin, Michael A.; Raymond, F. Lucy

doi:10.1172/jci79765

Cited by 68 publications

(110 citation statements)

References 52 publications

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“…Several of these proteins are required for distinct synaptic functions; for example, synaptotagmin is required for synaptic facilitation and maintenance of the readily releasable pool of synaptic vesicles (32, 33). Mutations in human synaptophysin are recognized in X‐linked intellectual disability and mutations in synaptotagmin‐1 are found in altered states of cognition and movement (15, 16). The extent of loss of these synaptic proteins in hippocampal and cortical tissues at autopsy of patients with AD parallels decreases in the number of synapses and correlates with decreases in premortem cognitive functions (4, 8).…”

Section: Discussionmentioning

confidence: 99%

Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease

et al. 2016

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Synaptic dysfunction occurs early in senile dementias, presumably as a result of decreased levels of functional synaptic proteins as found in autopsied brains of patients with Alzheimer's disease (AD) or frontotemporal dementia (FTD). Plasma neuronal-derived exosomes (NDEs) were recovered by precipitation and immunoabsorption from 12 patients with AD, 16 with FTD, and 28 controls in a cross-sectional study, and from 9 patients with AD, 10 with FTD, and 19 controls in a longitudinal study. Six synaptic proteins in NDE extracts were quantified by ELISAs and normalized for exosome amounts. NDE levels of synaptophysin, synaptopodin, synaptotagmin-2, and neurogranin were significantly lower in patients with FTD and AD than in controls, but those of growth-associated protein 43 and synapsin 1 were reduced only in patients with AD. Functionally relevant phosphorylation of synapsin 1 serine 9 was reduced in patients with FTD and AD, although total synapsin 1 protein was higher in FTD than in controls. NDE levels of synaptotagmin, synaptophysin, and neurogranin were decreased years before dementia in patients with FTD and AD. NDE levels of synaptopodin, synaptotagmin, and synaptophysin, but not of amyloid β-peptide 42 or P-T181-tau, were correlated significantly with cognition assessed by mini-mental state examination or AD assessment scale-cognitive subscale. NDE synaptic proteins may be useful preclinical indices and progression measures in senile dementias.-Goetzl, E. J., Kapogiannis, D., Schwartz, J. B., Lobach, I. V., Goetzl, L., Abner, E. L., Jicha, G. A., Karydas, A. M., Boxer, A., Miller, B. L. Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease

et al. 2016

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“…Recently, a de novo syt1 missense mutation has been identified in an individual with severe motor and cognitive impairments (Baker et al, 2015). Expression of this mutant syt1 in mouse neurons revealed slowed synaptic vesicle fusion kinetics and faster endocytosis.…”

Section: Snare-associated Proteinsmentioning

confidence: 99%

Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets

Kavalali

2017

Pharmacol Rev

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“…CSPα/HSP70/SGT chaperone system, which maintains SNAP25 in a functional conformation, and α-synuclein, a small SV interactor that controls synaptobrevin 2, are causally involved in neurodegenerative disorders (13)(14)(15); (d) variants of genes encoding the RIM interactor PNKD or the SNAP25 and synaptotagmin interactor PRRT2 lead to dyskinesia (16)(17)(18); and (e) a variant of the gene encoding synaptotagmin 1, the Ca 2+ sensor required for evoked, synchronous SV fusion, was recently identified in a patient with motor and cognitive impairments (19). Beyond these examples, genome-wide association studies and analyses of gene copy number variations and of single-nucleotide polymorphisms in patients suggest a link between the dysfunction of presynaptic proteins and multiple neurological and psychiatric disorders (20)(21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder

Lipstein

Verhoeven‐Duif

Michelassi

et al. 2017

Journal of Clinical Investigation

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Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling

Cited by 68 publications

References 52 publications

Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease

Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease

Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets

Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder

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