UNC13A

Function

This gene encodes a member of the UNC13 family. UNC13A plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. It is involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and participates in the activity-dependent refilling of readily releasable vesicle pool. In Drosophila melanogaster, the protein has been shown to define the vesicle release site by regulating the coupling distance between synaptic vesicles and calcium channels in cooperation with another isoform, UNC13B. It is particularly important in most glutamatergic-mediated synapses as well as GABA-mediated synapses. It plays a role in dendrite formation by melanocytes and in secretory granule priming in insulin secretion.

Protein structure

Several conserved domains have been found in UNC13A. These conserved domains include three C2 domains. One C2 domain is centrally located, another is at the carboxyl end, and there is a third. In addition, there is one C1 domain, as well as Munc13 homology domains 1 (MHD1) and 2 (MHD2).

Subcellular location

UNC13A is localized to the active zone of presynaptic density. It is translocated to the plasma membrane in response to phorbol ester binding.

Interaction

UNC13A has been shown to interact with:

• STX1A,
• STX1B1,
• DOC2A,
• BSN,
• RIMS1,
• RIMS2,
• ERC2, and
• RAB3A.

Clinical significance

Single nucleotide polymorphisms in this gene may be associated with sporadic amyotrophic lateral sclerosis. This single nucleotide polymorphism has been discovered on chromosome 19. This variation of the single nucleotide involving UNC13A has also been implicated in frontotemporal dementia (FTD). Pathology of TDP-43 in both ALS and FTD results in a cryptic exon being expressed in UNC13A, which is exercerbated by the single nucleotide polymorphisms associated with ALS and FTD risk. This gene has also been associated with Alzheimer's disease (AD).

References

• Entrez Gene: Unc-13 homolog A (Homo Sapiens)
• Entrez Gene: Unc-13 homolog A (Mus musculus)
• Böhme MA, Beis C, Reddy-Alla S, Reynolds E, Mampell MM, Grasskamp AT, Lützkendorf J, Bergeron DD, Driller JH, Babikir H, Göttfert F, Robinson IM, O'Kane CJ, Hell SW, Wahl MC, Stelzl U, Loll B, Walter AM, Sigrist SJ, 6, Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca(2+) channel-vesicle coupling, Nature Neuroscience, 19, 10, 1311–1320, October 2016, 27526206, 10.1038/nn.4364, 11858/00-001M-0000-002B-2236-2, 8897877, free
• UNC13A - Protein unc-13 homolog A - Homo sapiens (Human) - UNC13A gene & protein, www.uniprot.org
• NCBI Conserved Domain Search, www.ncbi.nlm.nih.gov, 2016-05-06
• van Es MA, Veldink JH, Saris CG, Blauw HM, van Vught PW, Birve A, Lemmens R, Schelhaas HJ, Groen EJ, Huisman MH, van der Kooi AJ, de Visser M, Dahlberg C, Estrada K, Rivadeneira F, Hofman A, Zwarts MJ, van Doormaal PT, Rujescu D, Strengman E, Giegling I, Muglia P, Tomik B, Slowik A, Uitterlinden AG, Hendrich C, Waibel S, Meyer T, Ludolph AC, Glass JD, Purcell S, Cichon S, Nöthen MM, Wichmann HE, Schreiber S, Vermeulen SH, Kiemeney LA, Wokke JH, Cronin S, McLaughlin RL, Hardiman O, Fumoto K, Pasterkamp RJ, Meininger V, Melki J, Leigh PN, Shaw CE, Landers JE, Al-Chalabi A, Brown RH, Robberecht W, Andersen PM, Ophoff RA, van den Berg LH, 6, Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis, Nature Genetics, 41, 10, 1083–1087, October 2009, 19734901, 10.1038/ng.442, 8659710
• Bosco DA, Landers JE, Genetic determinants of amyotrophic lateral sclerosis as therapeutic targets, CNS & Neurological Disorders Drug Targets, 9, 6, 779–790, December 2010, 20942785, 10.2174/187152710793237494
• Su XW, Broach JR, Connor JR, Gerhard GS, Simmons Z, Genetic heterogeneity of amyotrophic lateral sclerosis: implications for clinical practice and research, Muscle & Nerve, 49, 6, 786–803, June 2014, 24488689, 10.1002/mus.24198, 38375893
• Finsterer J, Burgunder JM, Recent progress in the genetics of motor neuron disease, European Journal of Medical Genetics, 57, 2–3, 103–112, February 2014, 24503148, 10.1016/j.ejmg.2014.01.002, free
• Ma XR, Prudencio M, Koike Y, Vatsavayai SC, Kim G, Harbinski F, Briner A, Rodriguez CM, Guo C, Akiyama T, Schmidt HB, Cummings BB, Wyatt DW, Kurylo K, Miller G, Mekhoubad S, Sallee N, Mekonnen G, Ganser L, Rubien JD, Jansen-West K, Cook CN, Pickles S, Oskarsson B, Graff-Radford NR, Boeve BF, Knopman DS, Petersen RC, Dickson DW, Shorter J, Myong S, Green EM, Seeley WW, Petrucelli L, Gitler AD, 6, TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A, Nature, 603, 7899, 124–130, March 2022, 35197626, 10.1038/s41586-022-04424-7, 8891019, 2022Natur.603..124M
• Brown AL, Wilkins OG, Keuss MJ, Hill SE, Zanovello M, Lee WC, Bampton A, Lee FC, Masino L, Qi YA, Bryce-Smith S, Gatt A, Hallegger M, Fagegaltier D, Phatnani H, Newcombe J, Gustavsson EK, Seddighi S, Reyes JF, Coon SL, Ramos D, Schiavo G, Fisher EM, Raj T, Secrier M, Lashley T, Ule J, Buratti E, Humphrey J, Ward ME, Fratta P, 6, TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A, Nature, 603, 7899, 131–137, March 2022, 35197628, 10.1038/s41586-022-04436-3, 8891020, 2022Natur.603..131B
• Diekstra FP, Van Deerlin VM, van Swieten JC, Al-Chalabi A, Ludolph AC, Weishaupt JH, Hardiman O, Landers JE, Brown RH, van Es MA, Pasterkamp RJ, Koppers M, Andersen PM, Estrada K, Rivadeneira F, Hofman A, Uitterlinden AG, van Damme P, Melki J, Meininger V, Shatunov A, Shaw CE, Leigh PN, Shaw PJ, Morrison KE, Fogh I, Chiò A, Traynor BJ, Czell D, Weber M, Heutink P, de Bakker PI, Silani V, Robberecht W, van den Berg LH, Veldink JH, 6, C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis, Annals of Neurology, 76, 1, 120–133, July 2014, 24931836, 4137231, 10.1002/ana.24198
• Hartlage-Rübsamen M, Waniek A, Roßner S, Munc13 genotype regulates secretory amyloid precursor protein processing via postsynaptic glutamate receptors, International Journal of Developmental Neuroscience, 31, 1, 36–45, February 2013, 23070049, 10.1016/j.ijdevneu.2012.10.001, 28216850

Further reading

• Augustin I, Rosenmund C, Südhof TC, Brose N, Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles, Nature, 400, 6743, 457–461, July 1999, 10440375, 10.1038/22768, 4364774, 1999Natur.400..457A
• Betz A, Ashery U, Rickmann M, Augustin I, Neher E, Südhof TC, Rettig J, Brose N, 6, Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release, Neuron, 21, 1, 123–136, July 1998, 9697857, 10.1016/s0896-6273(00)80520-6, free, 15707959, 11858/00-001M-0000-0012-FC62-6
• Betz A, Thakur P, Junge HJ, Ashery U, Rhee JS, Scheuss V, Rosenmund C, Rettig J, Brose N, 6, Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming, Neuron, 30, 1, 183–196, April 2001, 11343654, 10.1016/s0896-6273(01)00272-0, free, 155875, 11858/00-001M-0000-0012-F596-C
• Huang CC, Yang DM, Lin CC, Kao LS, Involvement of Rab3A in vesicle priming during exocytosis: interaction with Munc13-1 and Munc18-1, Traffic, 12, 10, 1356–1370, October 2011, 21689256, 10.1111/j.1600-0854.2011.01237.x, free
• Koch H, Hofmann K, Brose N, Definition of Munc13-homology-domains and characterization of a novel ubiquitously expressed Munc13 isoform, The Biochemical Journal, 349, Pt 1, 247–253, July 2000, 10861235, 1221144, 10.1042/0264-6021:3490247
• Lavi A, Sheinin A, Shapira R, Zelmanoff D, Ashery U, DOC2B and Munc13-1 differentially regulate neuronal network activity, Cerebral Cortex, 24, 9, 2309–2323, September 2014, 23537531, 4128701, 10.1093/cercor/bht081
• Ohtsuka T, Takao-Rikitsu E, Inoue E, Inoue M, Takeuchi M, Matsubara K, Deguchi-Tawarada M, Satoh K, Morimoto K, Nakanishi H, Takai Y, 6, Cast: a novel protein of the cytomatrix at the active zone of synapses that forms a ternary complex with RIM1 and munc13-1, The Journal of Cell Biology, 158, 3, 577–590, August 2002, 12163476, 2173811, 10.1083/jcb.200202083