SNAREs and developmental disorders

Tang, Bor Luen

doi:10.1002/jcp.30067

Cited by 19 publications

(9 citation statements)

References 310 publications

(432 reference statements)

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“…These complexes are also necessary for learning, movement, memory formation, and normal brain function. Indeed, optimal levels of SNAP-25 are important for neurotransmission, and changes in SNAP-25 expression may contribute to the pathophysiology of various diseases, including Alzheimer's disease, schizophrenia, autism, and ADHD (Kim et al, 2007 ; Najera et al, 2019 ; Tang, 2021 ; Wang et al, 2021 ). Notably, genes for SNAP-25 and other SNARE complex proteins have been demonstrated to be associated with susceptibility and working memory in male patients with ADHD.…”

Section: Discussionmentioning

confidence: 99%

Synaptosomal-Associated Protein 25 Gene Polymorphisms Affect Treatment Efficiency of Methylphenidate in Children With Attention-Deficit Hyperactivity Disorder: An fNIRS Study

Yan

et al. 2022

Front. Behav. Neurosci.

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Methylphenidate (MPH) is the first-line drug for the treatment of children with attention-deficit hyperactivity disorder (ADHD); however, individual curative effects of MPH vary. Many studies have demonstrated that synaptosomal-associated protein 25 (SNAP-25) gene MnlI polymorphisms may be related to the efficacy of MPH. However, the association between SNAP-25MnlI polymorphisms and changes in brain hemodynamic responses after MPH treatment is still unclear. This study used functional near-infrared spectroscopy (fNIRS) to preliminarily investigate the interaction of MPH treatment-related prefrontal inhibitory functional changes with the genotype status of the SNAP-25 gene in children with ADHD. In total, 38 children with ADHD aged 6.76–12.08 years were enrolled in this study and divided into the following two groups based on SNAP-25 gene MnlI polymorphisms: T/T genotype group (wild-type group, 27 children) and G allele carrier group (mutation group, 11 children). The averaged oxygenated hemoglobin concentration changes [Δavg oxy-Hb] and deoxyhemoglobin concentration changes [Δavg deoxy-Hb] in the frontal cortex before MPH treatment and after 1.5 h (post-MPH1.5h) and 4 weeks (post-MPH4w) of MPH treatments were monitored using fNIRS during the go/no-go task. SNAP-IV scores were evaluated both pre-MPH and post-MPH4w treatments. In the T/T genotype group, [Δavg oxy-Hb] in the dorsolateral prefrontal cortex was significantly higher after 4 weeks of MPH (post-MPH4W) treatment than pre-treatment; however, in the G allele group, no significant differences in [Δavg oxy-Hb] were observed between pre- and post-treatments. In the go/no-go task, the accuracy was significantly increased post-MPH4w treatment in the T/T genotype group, while no significant differences were observed in response time and accuracy of the “go” sand no-go task in the G allele group for pre-MPH, post-MPH1.5h, and post-MPH4w treatments. The T/T genotype group exhibited a significant decrease in SNAP-IV scores after MPH treatment, while the G allele group showed no significant difference. In conclusion, fNIRS data combined with SNAP-25 MnlI polymorphism analysis may be a useful biomarker for evaluating the effects of MPH in children with ADHD.

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Section: Discussionmentioning

confidence: 99%

Synaptosomal-Associated Protein 25 Gene Polymorphisms Affect Treatment Efficiency of Methylphenidate in Children With Attention-Deficit Hyperactivity Disorder: An fNIRS Study

Yan

et al. 2022

Front. Behav. Neurosci.

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“…Earlier studies reported that mutations in the components of the canonical synaptic vesicle fusion SNARE complex ( VAMP2 , STX1, and SNAP25) inhibit docking of the vesicle preventing the exocytosis of neurotransmitters and release of AGRN ligand protein into the synaptic cleft [ 3 , 4 ] (Figures 1A - 1B ). This explains the role of VAMP2 variants in impaired neurodevelopment [ 6 ] and AGRN mutations in causing CMS [ 7 , 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…Proper formation of the SNARE complex in the postsynaptic membrane facilitates the exocytosis of neurotransmitters into the synaptic cleft [ 1 ]. Mutations in the components of the canonical synaptic vesicle fusion SNARE complex ( VAMP2 , STX1, and SNAP25) produce variant phenotypes of autism, intellectual disability, movement disorders, and epilepsy [ 3 ]. Specific de novo heterozygous VAMP2 mutations in distinct individuals present with neurodevelopmental disorder characterized by axial hypotonia, intellectual disability, autistic features along with central visual impairment, hyperkinetic movement disorder, and epilepsy [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Unfolding of Novel Independent Missense Mutations in VAMP2 and AGRN and Their Collective Role in Global Developmental Delay: A Case Report

Heidarpour¹,

Singh²,

Caputo³

et al. 2022

Cureus

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Vesicle-associated membrane protein 2 ( VAMP2 ) and Agrin ( AGRN ) are crucial proteins in neurotransmission. VAMP2 is a vesicular protein that facilitates the exocytosis of neurotransmitters. At the same time, AGRN plays a critical role in the maintenance and function of neuromuscular junctions. Mutations in the signaling pathway of VAMP2 and AGRN impair proper signaling between the presynaptic and postsynaptic neurons, and can result in neurodevelopmental conditions known as global developmental delay (GDD). This study highlights a presentation of GDD in a patient with concurrent mutations in VAMP2 and AGRN . A three-year-old female child presented with GDD characterized by hypotonia, intellectual disability, and dysphagia. Physical exam exhibited signs of developmental delay and severe muscle weakness. EEG findings were suggestive of a hypsarrhythmia pattern. The ophthalmological evaluation showed partial optic atrophy bilaterally. Therapeutic interventions included Keppra and Topamax, which proved ineffective. The patient’s outcome was inconclusive as care was transferred to another facility. This case study reports the novel appearance of two concurrent mutations: p.Gln76Pro associated with VAMP2 and p.Gln970Glu associated with AGRN . Mutations in VAMP2 lead to a dysfunctional SNARE complex and inhibit exocytosis of neurotransmitters into the synaptic cleft. Mutations in AGRN impair the ability to form and activate postsynaptic nicotinic acetylcholine receptors. Improper signaling between presynaptic and postsynaptic neurons is an important determinant of GDD. We hope that accounting for this mutational pattern will contribute to understanding synapse assembly and help unravel the complex interplay of factors involved in the pathology of neuromuscular disorders and GDD.

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“…Another important group of conditions that show marked clinical overlap with disorders of autophagy are disorders of intracellular (vesicular) trafficking, probably reflective of the fact that some of the proteins implicated in congenital disorders of autophagy, such as EPG5, do have genuinely multiple roles in both autophagy but also other, in particular endosomal/endocytic trafficking pathways [ 194 ]. Indeed, it may be very difficult to distinguish which of the phenotypical expressions of a mutated protein may be due to its role in autophagic or other closely related vesicular trafficking processes.…”

Section: Congenital Disorders Of Autophagymentioning

confidence: 99%

The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy

et al. 2021

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Primary dysfunction of autophagy due to Mendelian defects affecting core components of the autophagy machinery or closely related proteins have recently emerged as an important cause of genetic disease. This novel group of human disorders may present throughout life and comprises severe early-onset neurodevelopmental and more common adult-onset neurodegenerative disorders. Early-onset (or congenital) disorders of autophagy often share a recognizable “clinical signature,” including variable combinations of neurological, neuromuscular and multisystem manifestations. Structural CNS abnormalities, cerebellar involvement, spasticity and peripheral nerve pathology are prominent neurological features, indicating a specific vulnerability of certain neuronal populations to autophagic disturbance. A typically biphasic disease course of late-onset neurodegeneration occurring on the background of a neurodevelopmental disorder further supports a role of autophagy in both neuronal development and maintenance. Additionally, an associated myopathy has been characterized in several conditions. The differential diagnosis comprises a wide range of other multisystem disorders, including mitochondrial, glycogen and lysosomal storage disorders, as well as ciliopathies, glycosylation and vesicular trafficking defects. The clinical overlap between the congenital disorders of autophagy and these conditions reflects the multiple roles of the proteins and/or emerging molecular connections between the pathways implicated and suggests an exciting area for future research. Therapy development for congenital disorders of autophagy is still in its infancy but may result in the identification of molecules that target autophagy more specifically than currently available compounds. The close connection with adult-onset neurodegenerative disorders highlights the relevance of research into rare early-onset neurodevelopmental conditions for much more common, age-related human diseases. Abbreviations: AC: anterior commissure; AD: Alzheimer disease; ALR: autophagic lysosomal reformation; ALS: amyotrophic lateral sclerosis; AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; ASD: autism spectrum disorder; ATG: autophagy related; BIN1: bridging integrator 1; BPAN: beta-propeller protein associated neurodegeneration; CC: corpus callosum; CHMP2B: charged multivesicular body protein 2B; CHS: Chediak-Higashi syndrome; CMA: chaperone-mediated autophagy; CMT: Charcot-Marie-Tooth disease; CNM: centronuclear myopathy; CNS: central nervous system; DNM2: dynamin 2; DPR: dipeptide repeat protein; DVL3: disheveled segment polarity protein 3; EPG5: ectopic P-granules autophagy protein 5 homolog; ER: endoplasmic reticulum; ESCRT: homotypic fusion and protein sorting complex; FIG4: FIG4 phosphoinositide 5-phosphatase; FTD: frontotemporal dementia; GBA: glucocerebrosidase; GD: Gaucher disease; GRN: progranulin; GSD: glycogen storage disorder; HC: hippocampal commissure; HD: Huntington disease;...

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SNAREs and developmental disorders

Cited by 19 publications

References 310 publications

Synaptosomal-Associated Protein 25 Gene Polymorphisms Affect Treatment Efficiency of Methylphenidate in Children With Attention-Deficit Hyperactivity Disorder: An fNIRS Study

Synaptosomal-Associated Protein 25 Gene Polymorphisms Affect Treatment Efficiency of Methylphenidate in Children With Attention-Deficit Hyperactivity Disorder: An fNIRS Study

Unfolding of Novel Independent Missense Mutations in VAMP2 and AGRN and Their Collective Role in Global Developmental Delay: A Case Report

The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy

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