Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026838 (spasticity)
 6,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Clostridium botulinum neurotoxins (BoNTs) A and C1 cleave specific proteins required for neuroexocytosis. We demonstrated that, in intact neurons, BoNT A cleaves 25-kDa synaptosomal-associated protein (SNAP-25), and BoNT C1 cleaves both syntaxin and SNAP-25 (Williamson et al.: Mol Biol Cell 6:61a, 1995; J Biol Chem 271:7694-7699, 1996). Here, we compare the actions of BoNT A and BoNT C1 on mature and developing mouse spinal cord neurons in cell culture and demonstrate that BoNT C1 is severely neurotoxic. In mature cultures, synaptic terminals become enlarged shortly after BoNT C1 exposure, and, subsequently, axons, dendrites, and cell bodies degenerate. Electron microscopy confirms that early degenerative changes occur in synaptic terminals when the somatic cytoplasm appears normal. In newly plated cultures, few neurons survive exposure to BoNT C1. Whereas both BoNT A and BoNT C1 cleave SNAP-25, BoNT A has no adverse effect on neurite outgrowth, synaptogenesis, or neuron survival. This cytotoxicity is unique to BoNT C1, is specific to neurons, and is initiated at the synaptic terminal, suggesting either a novel role for syntaxin or additional actions of BoNT C1. The neurodegeneration induced by BoNT C1 may be significant in terms of its efficacy for the clinical treatment of dystonia and spasticity.
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PMID:Syntaxin and 25-kDa synaptosomal-associated protein: differential effects of botulinum neurotoxins C1 and A on neuronal survival. 963 13

We examined immunohistochemically the expression and localisation of synapse-associated proteins, syntaxin (SNT) and synaptotagmin (STG) in the entire resected specimens of colon obtained at the time of pull-through operation from 15 patients with Hirschsprung's disease (HD) and 6 age-matched controls. Both antibodies showed a similar pattern of staining. In the normal colon and ganglionic colon from HD, there was strong reactivity in the submucous and myenteric plexuses in addition to staining of nerve fibres in the smooth-muscle layers. In the aganglionic colon, there was an absence or marked decrease in SNT and STG-positive nerve fibres in the smooth-muscle layers and in hypertrophic nerve trunks. Our data indicate that important proteins necessary for the docking of synaptic vesicles at the presynaptic plasma membrane are lost in fibres innervating the smooth muscle of HD and suggest that abnormal neurotransmission may have a role in the maintenance of muscle spasticity.
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PMID:Lack of a docking mechanism for neurotransmitter release in the aganglionic segment of bowel in patients with Hirschsprung's disease. 979 80

STXBP1, also known as Munc-18, is a master regulator of neurotransmitter release and synaptic function in the human brain through its direct interaction with syntaxin 1A. STXBP1 binds syntaxin 1A is an inactive conformational state. STXBP1 decreases its binding affinity to syntaxin upon phosphorylation, enabling syntaxin 1A to engage in the SNARE complex, leading to neurotransmitter release. STXBP1-related disorders are well characterized by encephalopathy with epilepsy, and a diverse range of neurological and neurodevelopmental conditions. Through exome sequencing of a child with developmental delay, hypotonia, and spasticity, we found a novel de novo insertion mutation of three nucleotides in the STXBP1 coding region, resulting in an additional arginine after position 39 (R39dup). Inconclusive results from state-of-the-art variant prediction tools mandated a structure-based approach using molecular dynamics (MD) simulations of the STXBP1-syntaxin 1A complex. Comparison of the interaction interfaces of the wild-type and the R39dup complexes revealed a reduced interaction surface area in the mutant, leading to destabilization of the protein complex. Moreover, the decrease in affinity toward syntaxin 1A is similar for the phosphorylated STXBP1 and the R39dup. We applied the same MD methodology to seven additional previously reported STXBP1 mutations and reveal that the stability of the STXBP1-syntaxin 1A interface correlates with the reported clinical phenotypes. This study provides a direct link between the outcome of a novel variant in STXBP1 and protein structure and dynamics. The structural change upon mutation drives an alteration in synaptic function.
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PMID:De novo STXBP1 mutation in a child with developmental delay and spasticity reveals a major structural alteration in the interface with syntaxin 1A. 3281 82