Genomes and Genes
Gene Symbol: UNC13A
Description: unc-13 homolog A
Alias: Munc13-1, protein unc-13 homolog A
- Zhao S, Mugabo Y, Iglesias J, Xie L, Delghingaro Augusto V, Lussier R, et al. α/β-Hydrolase domain-6-accessible monoacylglycerol controls glucose-stimulated insulin secretion. Cell Metab. 2014;19:993-1007 pubmed publisher..Monoacylglycerol binds and activates the vesicle priming protein Munc13-1, thereby inducing insulin exocytosis. We propose saturated monoacylglycerol as a signal for GSIS and ABHD6 as a negative modulator of insulin secretion. ..
- VÃ©riÃ¨pe J, Fossouo L, Parker J. Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons. Nat Commun. 2015;6:7319 pubmed publisher..The human orthologue of UNC-13, UNC13A, has been identified as a genetic modifier of survival in ALS, and we provide functional evidence of UNC-13/UNC13A ..
- Lorenzoni P, Scola R, Kay C, Werneck L, Horvath R, Lochmuller H. How to Spot Congenital Myasthenic Syndromes Resembling the Lambert-Eaton Myasthenic Syndrome? A Brief Review of Clinical, Electrophysiological, and Genetics Features. Neuromolecular Med. 2018;20:205-214 pubmed publisher..We believe that CMS-LEMS must be included as an important diagnostic clue to genetic investigation in the diagnostic algorithms to CMS. We briefly review the main features of CMS-LEMS. ..
- Poursharifi P, Madiraju S, Prentki M. Monoacylglycerol signalling and ABHD6 in health and disease. Diabetes Obes Metab. 2017;19 Suppl 1:76-89 pubmed publisher..The purpose of this review is to provide a comprehensive summary of the current state of knowledge regarding ABHD6/MAG signalling and its possible therapeutic implications. ..
- Huang C, Chiu T, Lee T, Hsieh H, Lin C, Kao L. Soluble α-synuclein facilitates priming and fusion by releasing Ca2+ from the thapsigargin-sensitive Ca2+ pool in PC12 cells. J Cell Sci. 2018;131: pubmed publisher..mechanism by which α-synuclein interacts with regulatory proteins, including Rab3A, Munc13-1 (also known as Unc13a) and Munc18-1 (also known as STXBP1), in order to regulate exocytosis...
- Placek K, Baer G, Elman L, McCluskey L, Hennessy L, Ferraro P, et al. UNC13A polymorphism contributes to frontotemporal disease in sporadic amyotrophic lateral sclerosis. Neurobiol Aging. 2019;73:190-199 pubmed publisher..The genetic polymorphism rs12608932 in UNC13A confers increased risk of sporadic ALS and sporadic FTD and modifies survival in ALS...
- Engel A. Congenital Myasthenic Syndromes in 2018. Curr Neurol Neurosci Rep. 2018;18:46 pubmed publisher..Exome sequencing has provided a powerful tool for identifying novel CMS. Identifying the disease genes is essential for determining optimal therapy. The landscape of the CMS is still unfolding. ..
- Zhao S, Poursharifi P, Mugabo Y, Levens E, Vivot K, Attane C, et al. Î±/Î²-Hydrolase domain-6 and saturated long chain monoacylglycerol regulate insulin secretion promoted by both fuel and non-fuel stimuli. Mol Metab. 2015;4:940-50 pubmed publisher..ABHD6 regulates insulin secretion in response to fuel stimuli at large and some non-fuel stimuli by controlling long chain saturated 1-MAG levels that synergize with other signaling pathways for secretion. ..
- van Blitterswijk M, Mullen B, Wojtas A, Heckman M, Diehl N, Baker M, et al. Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene. Mol Neurodegener. 2014;9:38 pubmed publisher..001], rs13268953 [ELP3; p-value = 0.003], the epsilon 4 allele [APOE; p-value = 0.004], rs12608932 [UNC13A; p-value = 0.003], and rs1800435 [ALAD; p-value = 0.003])...
- Liu X, Seven A, Camacho M, Esser V, Xu J, Trimbuch T, et al. Functional synergy between the Munc13 C-terminal C1 and C2 domains. elife. 2016;5: pubmed publisher..Overall, our results support a model whereby the multiple domains of Munc13s cooperate to coordinate synaptic vesicle docking, priming and fusion. ..
- Yang X, Wang S, Sheng Y, Zhang M, Zou W, Wu L, et al. Syntaxin opening by the MUN domain underlies the function of Munc13 in synaptic-vesicle priming. Nat Struct Mol Biol. 2015;22:547-54 pubmed publisher..These results support the notion that orchestration of syntaxin-1 opening and SNARE-complex assembly underlies the central role of UNC-13-Munc13s in synaptic-vesicle priming. ..
- de Jong A, Meijer M, Saarloos I, Cornelisse L, Toonen R, Sørensen J, et al. Phosphorylation of synaptotagmin-1 controls a post-priming step in PKC-dependent presynaptic plasticity. Proc Natl Acad Sci U S A. 2016;113:5095-100 pubmed publisher..We conclude that synaptotagmin-1 phosphorylation is an essential step in PKC-dependent potentiation of synaptic transmission, acting downstream of the two other essential DAG/PKC substrates, Munc13-1 and Munc18-1. ..
- Gandasi N, Yin P, Riz M, Chibalina M, Cortese G, Lund P, et al. Ca2+ channel clustering with insulin-containing granules is disturbed in type 2 diabetes. J Clin Invest. 2017;127:2353-2364 pubmed publisher..Thus, rapid insulin secretion requires Munc13-mediated recruitment of L-type Ca2+ channels in close proximity to insulin granules. Loss of this organization underlies disturbed insulin secretion kinetics in T2D. ..
- Fan F, Matsunaga K, Wang H, Ishizaki R, Kobayashi E, Kiyonari H, et al. Exophilin-8 assembles secretory granules for exocytosis in the actin cortex via interaction with RIM-BP2 and myosin-VIIa. elife. 2017;6: pubmed publisher..This newly identified complex acts as a physical and functional scaffold and provides a mechanism supporting a releasable pool of granules within the F-actin network beneath the plasma membrane. ..
- Gioia D, Alexander N, McCool B. Differential Expression of Munc13-2 Produces Unique Synaptic Phenotypes in the Basolateral Amygdala of C57BL/6J and DBA/2J Mice. J Neurosci. 2016;36:10964-10977 pubmed..Importantly, these proteins also contain a large number of modulatory sites, making them attractive potential targets for the development of novel neuropharmaceutical treatments. ..
- van Eijk R, Jones A, Sproviero W, Shatunov A, Shaw P, Leigh P, et al. Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials. Neurology. 2017;89:1915-1922 pubmed publisher..We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months...
- Xu J, Camacho M, Xu Y, Esser V, Liu X, Trimbuch T, et al. Mechanistic insights into neurotransmitter release and presynaptic plasticity from the crystal structure of Munc13-1 C1C2BMUN. elife. 2017;6: pubmed publisher..The structure imposes key constraints for models of neurotransmitter release and suggests that Munc13-1 bridges the vesicle and plasma membranes from the periphery of the membrane-membrane interface. ..
- Wang S, Choi U, Gong J, Yang X, Li Y, Wang A, et al. Conformational change of syntaxin linker region induced by Munc13s initiates SNARE complex formation in synaptic exocytosis. EMBO J. 2017;36:816-829 pubmed publisher..We suggest that the conformational change of the syntaxin-1 linker region induced by Munc13-1 initiates ternary SNARE complex formation in the neuronal system. ..
- Pany S, Ghosh A, You Y, Nguyen N, Das J. Resveratrol inhibits phorbol ester-induced membrane translocation of presynaptic Munc13-1. Biochim Biophys Acta Gen Subj. 2017;1861:2640-2651 pubmed publisher..This study characterizes Munc13-1 as a target of resveratrol and highlights the importance of dietary polyphenol in the management of neurodegenerative diseases. ..
- Man K, Imig C, Walter A, Pinheiro P, Stevens D, Rettig J, et al. Identification of a Munc13-sensitive step in chromaffin cell large dense-core vesicle exocytosis. elife. 2015;4: pubmed publisher..Our data demonstrate that the molecular steps of SV and LDCV priming are very similar while SV and LDCV docking mechanisms are distinct. ..
- Petrie M, Esquibel J, Kabachinski G, Maciuba S, Takahashi H, Edwardson J, et al. The Vesicle Priming Factor CAPS Functions as a Homodimer via C2 Domain Interactions to Promote Regulated Vesicle Exocytosis. J Biol Chem. 2016;291:21257-21270 pubmed..The unique tandem C2-PH domain of CAPS may serve as a PI(4,5)P2-triggered switch for dimerization. CAPS dimerization may be coupled to oligomeric SNARE complex assembly for vesicle docking and priming. ..
- Sarath Babu N, Murthy C, Kakara S, Sharma R, Brahmendra Swamy C, Idris M. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's disease in zebrafish. Proteomics. 2016;16:1407-20 pubmed publisher..This zebrafish based PD model can be used as a potential model system for screening prospective drug molecules for PD. ..
- Fulterer A, Andlauer T, Ender A, Maglione M, Eyring K, Woitkuhn J, et al. Active Zone Scaffold Protein Ratios Tune Functional Diversity across Brain Synapses. Cell Rep. 2018;23:1259-1274 pubmed publisher..ELKS family Bruchpilot, BRP, and Syd-1) cluster-specific (M)Unc13 release factor isoforms either close (BRP/Unc13A) or further away (Syd-1/Unc13B) from VGCCs across synapses of the Drosophila olfactory system, resulting in ..
- Martin T. PI(4,5)Pâ‚‚-binding effector proteins for vesicle exocytosis. Biochim Biophys Acta. 2015;1851:785-93 pubmed publisher..Overall, focal vesicle exocytosis occurs at sites landmarked by PI(4,5)P2, which serves to recruit and/or activate multifunctional PI(4,5)Pâ‚‚-binding proteins. This article is part of a Special Issue entitled Phosphoinositides. ..
- Dekker A, Seelen M, van Doormaal P, van Rheenen W, Bothof R, van Riessen T, et al. Large-scale screening in sporadic amyotrophic lateral sclerosis identifies genetic modifiers in C9orf72 repeat carriers. Neurobiol Aging. 2016;39:220.e9-15 pubmed publisher..cases and 959 controls, analyzing 10 ALS genes: SOD1, C9orf72, TARDBP, FUS, ANG, CHMP2B, ATXN2, NIPA1, SMN1, and UNC13A. We observed sporadic cases with multiple genetic risk variants in 4.1% compared with 1.3% in controls...
- Böhme M, Beis C, Reddy Alla S, Reynolds E, Mampell M, Grasskamp A, et al. Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca(2+) channel-vesicle coupling. Nat Neurosci. 2016;19:1311-20 pubmed publisher..revealed that the Unc13B isoform was recruited to nascent AZs by the scaffolding proteins Syd-1 and Liprin-?, and Unc13A was positioned by Bruchpilot and Rim-binding protein complexes at maturing AZs...
- Kawabe H, Mitkovski M, Kaeser P, Hirrlinger J, Opazo F, Nestvogel D, et al. ELKS1 localizes the synaptic vesicle priming protein bMunc13-2 to a specific subset of active zones. J Cell Biol. 2017;216:1143-1161 pubmed publisher..Thus, synapse-specific interactions of different Munc13 isoforms with ELKS1 or RIMs are key determinants of the molecular and functional heterogeneity of presynaptic AZs. ..
- Vidal Taboada J, López López A, Salvado M, Lorenzo L, Garcia C, Mahy N, et al. UNC13A confers risk for sporadic ALS and influences survival in a Spanish cohort. J Neurol. 2015;262:2285-92 pubmed publisherTo investigate the association of functional variants of the human UNC13A gene with the risk of ALS, survival and the disease progression rate in a Spanish ALS cohort...
- Lai Y, Choi U, Leitz J, Rhee H, Lee C, Altas B, et al. Molecular Mechanisms of Synaptic Vesicle Priming by Munc13 and Munc18. Neuron. 2017;95:591-607.e10 pubmed publisher..Together, the physiological functions of Munc13 may be related to regulation of proper SNARE complex assembly. ..
- Ahmeti K, Ajroud Driss S, Al Chalabi A, Andersen P, Armstrong J, Birve A, et al. Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1. Neurobiol Aging. 2013;34:357.e7-19 pubmed publisher..Identifying the underlying pathways influencing susceptibility to and age at onset of ALS may provide insight into the pathogenic mechanisms and motivate new pharmacologic targets for this fatal neurodegenerative disease. ..
- Parsaud L, Li L, Jung C, Park S, Saw N, Park S, et al. Calcium-dependent activator protein for secretion 1 (CAPS1) binds to syntaxin-1 in a distinct mode from Munc13-1. J Biol Chem. 2013;288:23050-63 pubmed publisher..We also propose that the preferential binding of CAPS1 to open syntaxin-1 can contribute to the stabilization of the open state of syntaxin-1 during its transition from "closed" state to the SNARE complex formation. ..
- Diekstra F, Van Deerlin V, van Swieten J, Al Chalabi A, Ludolph A, Weishaupt J, et al. C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis. Ann Neurol. 2014;76:120-33 pubmed publisher..2 (lowest p = 2.6 Ã— 10(-12) ) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 Ã— 10(-11) ) as shared susceptibility loci for ALS and FTD-TDP...
- Bello O, Zanetti M, Mayorga L, Michaut M. RIM, Munc13, and Rab3A interplay in acrosomal exocytosis. Exp Cell Res. 2012;318:478-88 pubmed publisher..Our results suggest that the RIM/Munc13/Rab3 A complex participates in acrosomal exocytosis and that RIM and Rab3A have central roles in membrane docking...
- Rossner S, Fuchsbrunner K, Lange Dohna C, Hartlage Rübsamen M, Bigl V, Betz A, et al. Munc13-1-mediated vesicle priming contributes to secretory amyloid precursor protein processing. J Biol Chem. 2004;279:27841-4 pubmed..We establish that, in addition to PKC, Munc13-1 significantly contributes to the regulation of secretory APP metabolism. ..
- Yoo J, Lim T, Park J, Hah Y, Park N, Hong S, et al. SYT14L, especially its C2 domain, is involved in regulating melanocyte differentiation. J Dermatol Sci. 2013;72:246-51 pubmed publisher..These results suggest that SYT14L, especially its C2 domain, may play an important role in regulating melanocyte differentiation through the modulation of ERK and (or) CREB signaling. ..
- Takao Rikitsu E, Mochida S, Inoue E, Deguchi Tawarada M, Inoue M, Ohtsuka T, et al. Physical and functional interaction of the active zone proteins, CAST, RIM1, and Bassoon, in neurotransmitter release. J Cell Biol. 2004;164:301-11 pubmed..These results indicate that CAST serves as a key component of the CAZ structure and is involved in neurotransmitter release by binding these CAZ proteins. ..
- Das J, Kedei N, Kelsey J, You Y, Pany S, Mitchell G, et al. Critical role of Trp-588 of presynaptic Munc13-1 for ligand binding and membrane translocation. Biochemistry. 2017;: pubmed publisher..This study shows that Trp-588 is an important structural element for ligand binding and membrane translocation in Munc13-1...
- Fogh I, Ratti A, Gellera C, Lin K, Tiloca C, Moskvina V, et al. A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis. Hum Mol Genet. 2014;23:2220-31 pubmed publisher..Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci. ..
- Kwan E, Xie L, Sheu L, Ohtsuka T, Gaisano H. Interaction between Munc13-1 and RIM is critical for glucagon-like peptide-1 mediated rescue of exocytotic defects in Munc13-1 deficient pancreatic beta-cells. Diabetes. 2007;56:2579-88 pubmed..We had reported that haplodeficient Munc13-1(+/-) mouse islet beta-cells exhibited reduced insulin secretion, causing glucose intolerance. Munc13-1 binds Epac2 and Rim2, but their functional interactions remain unclear...
- Tada H, Okano H, Takagi H, Shibata S, Yao I, Matsumoto M, et al. Fbxo45, a novel ubiquitin ligase, regulates synaptic activity. J Biol Chem. 2010;285:3840-9 pubmed publisher..We also found that Fbxo45 induces the degradation of a synaptic vesicle-priming factor, Munc13-1. We propose that Fbxo45 plays an important role in the regulation of neurotransmission by modulating Munc13-1 at the synapse. ..
- Diekstra F, Van Vught P, van Rheenen W, Koppers M, Pasterkamp R, van Es M, et al. UNC13A is a modifier of survival in amyotrophic lateral sclerosis. Neurobiol Aging. 2012;33:630.e3-8 pubmed publisher..in patients with sporadic amyotrophic lateral sclerosis (ALS) showed that the common variant rs12608932 in gene UNC13A was associated with disease susceptibility. UNC13A regulates the release of neurotransmitters, including glutamate...
- Higashio H, Satoh Y, Saino T. Inhibitory role of Munc13-1 in antigen-induced mast cell degranulation. Biomed Res. 2017;38:321-329 pubmed publisher..These results suggested that Munc13-1 has an inhibitory role in antigen-induced mast cell degranulation, which is performed in a Munc13-4-dependent manner...
- ChiÃ² A, Mora G, Restagno G, Brunetti M, Ossola I, Barberis M, et al. UNC13A influences survival in Italian amyotrophic lateral sclerosis patients: a population-based study. Neurobiol Aging. 2013;34:357.e1-5 pubmed publisherThe common variant rs12608932, located within an intron of UNC13A gene on chromosome 19p13...
- Park S, Bin N, Yu B, Wong R, Sitarska E, Sugita K, et al. UNC-18 and Tomosyn Antagonistically Control Synaptic Vesicle Priming Downstream of UNC-13 in Caenorhabditis elegans. J Neurosci. 2017;37:8797-8815 pubmed publisher..Thus, our study provides novel mechanistic insights into how Munc18/UNC-18 primes synaptic vesicle release and how this protein interacts functionally with Munc13/UNC-13 and Tomosyn/TOM-1. ..
- Lipstein N, Verhoeven Duif N, Michelassi F, Calloway N, van Hasselt P, Pieńkowska K, et al. Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder. J Clin Invest. 2017;127:1005-1018 pubmed publisher..shown that this condition is associated with a rare, de novo Pro814Leu variant in the major human Munc13 paralog UNC13A (also known as Munc13-1)...
- Reddy Alla S, Böhme M, Reynolds E, Beis C, Grasskamp A, Mampell M, et al. Stable Positioning of Unc13 Restricts Synaptic Vesicle Fusion to Defined Release Sites to Promote Synchronous Neurotransmission. Neuron. 2017;95:1350-1364.e12 pubmed publisher..Here, we identify that the (M)Unc13-family member Unc13A generates release sites and show the physiological relevance of their restrictive AZ targeting...
- Gaastra B, Shatunov A, Pulit S, Jones A, Sproviero W, Gillett A, et al. Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2016;17:593-599 pubmed..05 were selected for association testing. Analysis was by burden testing using SKAT. Candidate survival genes UNC13A, KIFAP3, and EPHA4 were tested for association in a UK sample comprising 25 short survivors and 25 long survivors...
- Okamoto Y, Lipstein N, Hua Y, Lin K, Brose N, Sakaba T, et al. Distinct modes of endocytotic presynaptic membrane and protein uptake at the calyx of Held terminal of rats and mice. elife. 2016;5: pubmed publisher..Our data identify a novel mechanism of stimulus- and Ca(2+)-dependent regulation of coordinated endocytosis of synaptic membranes and vesicle proteins. ..