Affinage

UNC13A

Protein unc-13 homolog A · UniProt Q9UPW8

Length
1703 aa
Mass
193.0 kDa
Annotated
2026-04-28
91 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UNC13A (Munc13-1) is an essential presynaptic active zone protein that primes synaptic vesicles to a fusion-competent state by opening syntaxin-1 from its closed conformation and cooperatively chaperoning SNARE complex assembly together with Munc18-1 via its MUN domain (PMID:10440375, PMID:15667202, PMID:31888993, PMID:32086964). Its elongated C1C2BMUNC2C structure bridges synaptic vesicle and plasma membranes through distinct membrane-binding faces, with the C2C domain capturing vesicles and the C1-C2B region sensing diacylglycerol, Ca²⁺, and PIP₂ to modulate release probability and short-term plasticity; self-assembly into nanoclusters at the active zone defines the number of independent release sites and clusters multiple SNARE complexes to synchronize fusion (PMID:30816091, PMID:34779770, PMID:29230050, PMID:38755165). Multiple autoinhibitory mechanisms—involving the polyE motif, C2A homodimerization, and CaM-binding domain interactions with the MUN domain—suppress priming activity until relieved by presynaptic Ca²⁺, RIM, and calmodulin, thereby coupling vesicle priming to synaptic activity and enabling presynaptic forms of short- and long-term plasticity (PMID:38417672, PMID:40489622, PMID:23770256, PMID:21849565). Germline coding variants in UNC13A cause a neurodevelopmental syndrome through loss-of-function, gain-of-function, or impaired second-messenger regulation of neurotransmission, while in ALS/FTD, nuclear loss of TDP-43 triggers cryptic exon inclusion in UNC13A mRNA leading to nonsense-mediated decay and UNC13A protein depletion, a process potentiated by common intronic risk SNPs (PMID:41125872, PMID:35197626, PMID:35197628).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1997 High

    Establishing how UNC13A contacts the exocytotic machinery: Munc13-1 was shown to directly bind the N-terminal domain of syntaxin-1 and associate with assembled SNARE complexes, placing it at the heart of vesicle fusion regulation.

    Evidence Three orthogonal biochemical binding assays (pulldown, co-IP, blot overlay) with syntaxin domain mapping

    PMID:8999968

    Open questions at the time
    • Whether syntaxin binding is sufficient for priming was unknown
    • The functional consequence of the Munc13-1–SNARE interaction was not tested in neurons
  2. 1998 High

    Identifying UNC13A as a DAG/phorbol ester receptor independent of PKC resolved how diacylglycerol second-messenger signaling directly potentiates neurotransmitter release at the presynaptic terminal.

    Evidence Direct phorbol ester binding assays; overexpression at Xenopus NMJ with electrophysiology

    PMID:9697857

    Open questions at the time
    • Whether DAG binding was required for the priming function per se was untested
    • Structural basis of DAG recognition was unknown
  3. 1999 High

    Knockout analysis definitively placed UNC13A at the vesicle priming step: Munc13-1-null neurons formed normal synapses but completely failed to generate a fusion-competent vesicle pool, blocking all physiological release while leaving latrotoxin-evoked release intact.

    Evidence Munc13-1 knockout mouse neurons; electrophysiology with multiple stimulation paradigms; electron microscopy

    PMID:10440375

    Open questions at the time
    • Whether Munc13-1 directly opens syntaxin was unknown
    • The minimal priming domain had not been defined
  4. 2001 High

    Discovery that RIM1 binding is required for Munc13-1 priming function established the RIM–Munc13 axis as a core active zone module, with disruption phenocopying Munc13-1 loss.

    Evidence Biochemical interaction assays and electrophysiology in cultured neurons with domain deletions

    PMID:11343654

    Open questions at the time
    • Structural basis of the RIM–Munc13 switch was unknown
    • Whether RIM controls Munc13-1 localization or activity was not distinguished
  5. 2005 High

    Mapping the minimal priming module to the C-terminal MUN-containing region (residues 1100–1735) and showing its dependence on syntaxin-1 binding established the domain architecture underlying Munc13-1's core catalytic function.

    Evidence Systematic deletion construct electrophysiology in chromaffin cells; point mutagenesis abolishing syntaxin binding

    PMID:16271475

    Open questions at the time
    • How the MUN domain opens syntaxin mechanistically was unresolved
    • Role of C2C domain in membrane bridging was unknown
  6. 2005 High

    The NMR structure of the C1 domain revealed that a conserved tryptophan occludes the DAG-binding pocket, explaining why Munc13-1 has lower DAG affinity than PKC and requires conformational change for activation.

    Evidence NMR structure determination; comparison with PKC C1 domain

    PMID:15667202

    Open questions at the time
    • Whether the occluded state serves as an autoinhibitory mechanism in vivo was unclear
  7. 2006 High

    Multiple studies in 2006 resolved the structural basis of the C2A homodimer/RIM heterodimer switch, demonstrated that RIM1α controls Munc13-1 active zone recruitment, and revealed rapid dynamic exchange of Munc13-1 at active zones—together establishing how Munc13-1 is targeted and retained at release sites.

    Evidence X-ray crystallography of C2A homodimer and C2A–RIM heterodimer; I121N mutagenesis in RIM1α KO mice; FRAP in Munc13-1-EYFP knockin mice

    PMID:16704978 PMID:16732694 PMID:17167095

    Open questions at the time
    • Whether homodimerization has an autoinhibitory role in vivo was not resolved
    • Full-length structural context was missing
  8. 2006 High

    Studies in pancreatic beta cells established a non-neuronal priming role for Munc13-1: heterozygous knockout mice showed impaired glucose-stimulated insulin secretion and abnormal glucose tolerance, with DAG-dependent priming required for sustained insulin release.

    Evidence Munc13-1 heterozygous KO and H567K knockin mice; patch-clamp capacitance in beta cells; glucose tolerance tests

    PMID:12871971 PMID:16644700 PMID:16697276

    Open questions at the time
    • Whether Munc13-1 regulates other non-neuronal secretory cell types was unknown
    • Relative contribution of Munc13-1 versus ubMunc13-2 in beta cells was not fully resolved
  9. 2007 High

    Activation of the C1 domain by phorbol ester increases vesicular release rate without affecting pool size, demonstrating that DAG signaling lowers the energy barrier for fusion rather than increasing the number of primed vesicles.

    Evidence Electrophysiology in H567K knockin mice with osmotic and Ca²⁺-triggered release paradigms

    PMID:17267576

    Open questions at the time
    • How C1 domain activation structurally communicates to the MUN domain was unknown
  10. 2011 High

    Demonstrating that Munc13-1 and the RIM1α–Munc13-1 interaction are required for presynaptic long-term potentiation at mossy fiber synapses established vesicle priming modulation as a substrate for long-term plasticity.

    Evidence Acute viral expression of Munc13-1 domain constructs; electrophysiology at hippocampal mossy fiber synapses

    PMID:21849565

    Open questions at the time
    • Whether other synapses use the same mechanism for presynaptic LTP was untested
    • The signaling cascade upstream of RIM–Munc13 during LTP was unresolved
  11. 2013 High

    Ca²⁺–calmodulin binding to Munc13-1 was shown to be a key determinant of short-term plasticity: knockin mice with a CaM-insensitive mutation showed slowed vesicle replenishment and aberrant depression, identifying Ca²⁺–CaM–Munc13-1 as the activity-dependent refilling signal.

    Evidence Knockin mouse (W464R) electrophysiology at calyx of Held

    PMID:23770256

    Open questions at the time
    • How CaM binding structurally modulates MUN domain activity was not known
    • Whether CaM-mediated regulation is conserved across synapse types was unclear
  12. 2016 High

    A human homozygous truncating mutation in UNC13A causing fatal microcephaly, cortical hyperexcitability, and myasthenia directly linked UNC13A loss-of-function to human disease through depletion of the readily releasable vesicle pool.

    Evidence Exome sequencing; in vitro microelectrode studies at the neuromuscular junction; electron microscopy

    PMID:27648472

    Open questions at the time
    • Whether partial loss-of-function variants produce milder phenotypes was unknown at the time
  13. 2017 High

    Super-resolution imaging revealed that Munc13-1 forms discrete nanoclusters that each constitute an independent release site, with the number of clusters determining synaptic weight—establishing a structural basis for how presynaptic strength is set.

    Evidence STED/STORM super-resolution microscopy with single-synapse glutamate imaging

    PMID:29230050

    Open questions at the time
    • Molecular determinants of cluster formation were unresolved
    • Minimum copy number per functional cluster was not defined in neurons
  14. 2017 High

    A de novo gain-of-function variant (P814L) in UNC13A was identified as the cause of a dyskinetic movement disorder, demonstrating that increased vesicle fusion propensity from a single amino acid change produces a dominant disease phenotype.

    Evidence Whole-exome sequencing; electrophysiology in murine neurons and C. elegans

    PMID:28192369

    Open questions at the time
    • Whether other gain-of-function variants produce similar phenotypes was unknown
    • Structural mechanism of P814L hyperactivity was not determined
  15. 2019 High

    Reconstitution and mutagenesis of the C1C2BMUNC2C region established that the C2C domain bridges vesicle and plasma membranes and is essential for docking, priming, and Ca²⁺-triggered release, completing the membrane-bridging model of Munc13-1 function.

    Evidence In vitro liposome bridging/fusion assays; C2C domain mutagenesis; electrophysiology in mouse neurons

    PMID:30816091

    Open questions at the time
    • Full-length structural context of membrane bridging was not available
    • How C2C cooperates with C1-C2B region in intact protein was modeled but not directly shown
  16. 2019 High

    Single-molecule force spectroscopy demonstrated that the MUN domain stabilizes the Munc18-1/syntaxin-1/VAMP2 template complex by ~2.1 kBT and promotes SNAP-25 binding, providing the first quantitative energetic framework for how Munc13-1 and Munc18-1 cooperatively chaperone SNARE assembly.

    Evidence Single-molecule force spectroscopy; SNARE assembly reconstitution with purified components

    PMID:31888993

    Open questions at the time
    • Whether additional regulatory domains modulate this cooperativity was not tested in this system
  17. 2020 High

    NMR and functional studies showed that Munc13-1 opens syntaxin-1 by acting on its linker region rather than the SNARE motif, clarifying the specific molecular step at which Munc13-1 converts syntaxin from closed to open conformation.

    Evidence NMR spectroscopy; SNARE complex assembly and liposome fusion assays with syntaxin linker mutations

    PMID:32086964

    Open questions at the time
    • Direct binding of the linker to Munc13-1 was barely detectable, suggesting a transient or catalytic mechanism not fully captured
  18. 2021 High

    Dissection of the C1-C2B region revealed two functionally separable membrane-binding faces: a polybasic face essential for Ca²⁺-independent priming and a DAG/Ca²⁺/PIP₂ face that modulates evoked release and plasticity, resolving how one domain integrates constitutive priming with activity-dependent modulation.

    Evidence Site-directed mutagenesis; liposome reconstitution; hippocampal electrophysiology

    PMID:34779770

    Open questions at the time
    • How these two faces are coordinated in vivo during trains of activity was not resolved
  19. 2021 High

    C2B domain knockin mice with bidirectional mutations established Ca²⁺-phospholipid binding at C2B as a core mechanism for activity-dependent vesicle replenishment, with enhanced binding accelerating recovery and impaired binding slowing it.

    Evidence Knockin mouse lines; electrophysiology at calyx of Held

    PMID:34706220

    Open questions at the time
    • Whether C2B Ca²⁺ sensing cooperates with CaM binding during high-frequency firing was not directly tested
  20. 2022 High

    Two independent studies demonstrated that TDP-43 nuclear depletion—a hallmark of ALS/FTD—causes cryptic exon inclusion in UNC13A mRNA leading to nonsense-mediated decay and loss of protein, with common intronic risk SNPs at TDP-43 binding sites potentiating mis-splicing, thereby linking UNC13A loss to neurodegeneration.

    Evidence TDP-43 knockdown in cell lines and iPSC-neurons; patient brain/spinal cord tissue; SNP functional reporter assays; RNA-seq

    PMID:35197626 PMID:35197628

    Open questions at the time
    • Whether UNC13A loss is causally sufficient for synaptic dysfunction in ALS was not yet shown with rescue experiments in peer-reviewed literature
    • Therapeutic targeting of the cryptic exon had not been validated in vivo
  21. 2023 High

    Additional RNA-binding proteins (hnRNP L, hnRNP A1, hnRNP A2B1) were identified as TDP-43-independent repressors of UNC13A cryptic exon inclusion, with hnRNP L levels inversely correlating with cryptic RNA burden in ALS/FTD brains, expanding the regulatory network controlling UNC13A mRNA integrity.

    Evidence RBP knockdown; RNA-immunoprecipitation; patient brain tissue correlation

    PMID:36930682

    Open questions at the time
    • Whether modulating these hnRNPs can therapeutically compensate for TDP-43 loss was not tested
    • Mechanism of TDP-43-independent repression was not structurally defined
  22. 2024 High

    Near-full-length Munc13-1 reconstitution revealed dual autoinhibitory mechanisms: the C2A domain and CaM-binding domain each independently suppress MUN domain activity, and are specifically relieved by RIM and calmodulin respectively, providing the first integrated autoinhibition model.

    Evidence Purification of near-full-length Munc13-1; liposome fusion reconstitution; NMR spectroscopy

    PMID:38417672

    Open questions at the time
    • Whether all inhibitory interactions are simultaneously engaged in the resting state was not determined
    • In vivo validation of the dual autoinhibition model was lacking
  23. 2024 High

    Single-vesicle reconstitution showed that Munc13-1 clusters multiple SNARE complexes at release sites to synchronize fusion pore opening, while Munc18-1 stoichiometrically engages trans-SNARE complexes to regulate zippering—revealing how both chaperones differentially control fusion pore properties.

    Evidence Single-vesicle fusion and single-molecule imaging reconstitution

    PMID:38755165

    Open questions at the time
    • Whether SNARE clustering by Munc13-1 controls quantal size in vivo was not tested
    • The minimum Munc13-1 copy number for functional clustering in neurons remains debated
  24. 2025 High

    The polyE motif unique to Munc13-1 was identified as a Ca²⁺-sensitive autoinhibitory element: it binds the MUN domain via electrostatic interactions and is displaced by ~40 µM Ca²⁺, providing a direct mechanism linking presynaptic Ca²⁺ influx to relief of Munc13-1 autoinhibition.

    Evidence In vitro binding and SNARE assembly assays; Ca²⁺ competition experiments; charge-reversal mutagenesis

    PMID:40489622

    Open questions at the time
    • In vivo relevance of polyE-mediated inhibition has not been tested with knockin animals
    • Whether polyE and C2A/CaM inhibitory mechanisms act sequentially or in parallel is unresolved
  25. 2025 High

    A comprehensive variant study established that germline UNC13A coding variants cause a neurodevelopmental syndrome through three distinct mechanisms—reduced synaptic strength, gain-of-function hyperactivation, and impaired second-messenger regulation—broadening the spectrum of UNC13A-associated disease.

    Evidence Patient cohort exome sequencing; variant expression in mouse hippocampal neurons and C. elegans with electrophysiology

    PMID:41125872

    Open questions at the time
    • Genotype-phenotype correlation for milder variants is incomplete
    • Whether compensatory mechanisms by other Munc13 isoforms modulate disease severity is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the full-length atomic structure of Munc13-1 in its autoinhibited and active conformations, in vivo validation of the polyE autoinhibitory mechanism, therapeutic efficacy of UNC13A cryptic exon-targeting ASOs in ALS/FTD animal models, and how Munc13-1 nanocluster stoichiometry is dynamically regulated during plasticity.
  • No full-length high-resolution structure exists
  • In vivo polyE knockin validation is lacking
  • ASO rescue of UNC13A cryptic exon has not been tested in animal models of ALS/FTD in peer-reviewed studies
  • How nanocluster copy number is regulated during plasticity is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 8 GO:0008289 lipid binding 5 GO:0005198 structural molecule activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 11 R-HSA-162582 Signal Transduction 7 R-HSA-5653656 Vesicle-mediated transport 6 R-HSA-1643685 Disease 4
Partners
CALM1DOC2BERC1RIMBP2RIMS1RIMS2STX1AUNC18A
Complex memberships
RIM1–Munc13-1–CAST active zone complexSNARE complex (syntaxin-1/SNAP-25/VAMP2)

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Munc13-1 (UNC13A) is essential for synaptic vesicle maturation/priming to fusion competence at glutamatergic synapses; knockout neurons form ultrastructurally normal synapses but vesicle cycle is arrested at the maturation step, blocking release by action potentials, calcium ionophores, and hypertonic sucrose, while alpha-latrotoxin-evoked release is preserved, indicating Munc13-1 acts specifically at the priming step. Munc13-1 knockout mouse neurons; electrophysiology; electron microscopy Nature High 10440375
1998 Munc13-1 is a presynaptic high-affinity phorbol ester and diacylglycerol receptor that associates with the plasma membrane upon phorbol ester binding and enhances neurotransmitter release when overexpressed presynaptically, acting in parallel with protein kinase C in the DAG second messenger pathway. Phorbol ester binding assays; overexpression in Xenopus neuromuscular junction; electrophysiology Neuron High 9697857
1997 Munc13-1 directly interacts with the N-terminal coiled-coil domain of syntaxin via its C-terminus, and through this interaction binds to a subpopulation of the exocytotic SNARE core complex (syntaxin/SNAP-25/synaptobrevin), implicating Munc13-1 in modulating SNARE complex formation for vesicle exocytosis. Three independent biochemical binding assays (pulldown, co-immunoprecipitation, blot overlay); syntaxin binding domain mapping The Journal of biological chemistry High 8999968
2001 Munc13-1 and RIM1 interact functionally at the active zone; disruption of the Munc13-1/RIM1 interaction causes loss of fusion-competent synaptic vesicles (phenocopying Munc13-1 deficiency), with RIM1 binding and vesicle priming mediated by two distinct structural modules of Munc13-1. Biochemical interaction assays; electrophysiology in cultured neurons; domain deletion analysis Neuron High 11343654
2006 Crystal structures of the Munc13-1 C2A domain homodimer (1.44 Å) and Munc13-1 C2A/RIM zinc-finger heterodimer (1.78 Å) reveal that the C2A domain can homodimerize via a four-stranded concave beta-sandwich, and that homodimerization competes with RIM heterodimerization, establishing a structural switch relevant to vesicle priming and presynaptic plasticity. X-ray crystallography guided by NMR spectroscopy; structural validation of competing interactions PLoS biology High 16732694
2005 The minimal Munc13-1 domain required for priming activity is the C-terminal region (residues 1100–1735) containing both Munc13-homology domains and the C-terminal C2 domain; priming requires interaction with Syntaxin 1, as point mutants unable to bind Syntaxin 1 cannot prime chromaffin granules. Deletion construct electrophysiology gain-of-function assay in chromaffin cells; point mutagenesis Current biology : CB High 16271475
2005 NMR structure of the Munc13-1 C1 domain reveals that a conserved tryptophan (Trp-22/Trp-588 in full-length) occludes the diacylglycerol/phorbol ester binding site—unlike PKC C1 domains—requiring a conformational change for ligand binding, explaining Munc13-1's lower DAG affinity compared to PKC. NMR structure determination; comparison with PKC C1 domain structures Biochemistry High 15667202
2007 Activation of the Munc13-1 C1 domain by phorbol ester (PDBu) increases the vesicular release rate without affecting readily releasable vesicle pool size, mechanistically lowering the energy barrier for vesicle fusion; the C1 domain mutant H567K is a gain-of-function that constitutively mimics the PDBu-activated state. Electrophysiology (osmotic release, Ca2+-triggered and spontaneous release assays); knockin mice expressing Munc13-1(H567K) The Journal of neuroscience : the official journal of the Society for Neuroscience High 17267576
2002 Munc13-1 forms a ternary complex with CAST and RIM1 at the cytomatrix of the active zone; CAST directly binds RIM1 and indirectly binds Munc13-1 through RIM1, and Bassoon associates with this complex, establishing a protein interaction network at the active zone. Co-immunoprecipitation; direct binding assays; immunolocalization The Journal of cell biology Medium 12163476
2006 Active zone recruitment of Munc13-1 and ubMunc13-2 is regulated by their binding to RIM1α; a single I121N point mutation in Munc13-1 abolishes RIM1α binding and prevents efficient synaptic recruitment; Munc13-1 levels are decreased in RIM1α-deficient brain and Munc13-1 is not properly enriched at active zones of mossy fiber terminals when RIM1α is absent. Point mutagenesis; in vitro binding assays; RIM1α knockout mice; immunohistochemistry; quantitative Western blot The Journal of biological chemistry High 16704978
2009 Domains of five active zone proteins (RIM1, Bassoon, CAST1/ELKS2, Aczonin/Piccolo, and Bassoon CC3) all converge on the N-terminal region of Munc13-1, establishing Munc13-1's N-terminus as a hub of protein–protein interactions at the active zone; expression of Aczonin-CC3 in neurons suppresses vesicle turnover. Yeast two-hybrid; pulldown assays; co-IP; expression of GFP fusion in neurons with functional readout The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 19812333
2013 Munc13-1 is a major presynaptic target of Ca2+–calmodulin signaling; knockin mice expressing Ca2+–calmodulin-insensitive Munc13-1(W464R) show slower synaptic vesicle replenishment, aberrant short-term depression, and reduced recovery after high-frequency stimulation, establishing Ca2+–calmodulin–Munc13-1 signaling as a key determinant of short-term synaptic plasticity. Knockin mouse electrophysiology at calyx of Held; Ca2+-calmodulin binding-deficient point mutation Neuron High 23770256
2017 Munc13-1 molecules form multiple discrete supramolecular self-assemblies in the presynaptic terminal that serve as independent vesicular release sites by recruiting syntaxin-1; multiplicity of these assemblies controls presynaptic synaptic weight in glutamatergic synapses. Single-synapse glutamate imaging; super-resolution (STED/STORM) microscopy of presynaptic proteins Nature neuroscience High 29230050
2017 A de novo Pro814Leu variant in UNC13A causes a dominant gain-of-function characterized by increased synaptic vesicle fusion propensity, increased initial release probability, and abnormal short-term plasticity, leading to a dyskinetic movement disorder in a human patient. Whole-exome sequencing; electrophysiology in murine neuronal cultures; functional analysis in C. elegans The Journal of clinical investigation High 28192369
2019 Munc13-1 bridges the synaptic vesicle and plasma membranes through opposite ends of its elongated C1C2BMUNC2C structure; mutations in the C2C domain membrane-binding sites disrupt liposome bridging and fusion in vitro and abolish synaptic vesicle docking, priming, and Ca2+-triggered release in mouse neurons, with a single residue substitution nearly completely abrogating release. In vitro liposome fusion/bridging assays; site-directed mutagenesis; electrophysiology in mouse neurons eLife High 30816091
2019 The MUN domain of Munc13-1 stabilizes the Munc18-1/syntaxin-1/VAMP2 template complex by ~2.1 kBT, enhancing SNAP-25 binding and subsequent full SNARE assembly; Munc13-1 and Munc18-1 cooperatively chaperone SNARE folding through a tetrameric complex. Single-molecule force spectroscopy; mutational analysis; in vitro SNARE assembly assays Proceedings of the National Academy of Sciences of the United States of America High 31888993
2006 FRAP experiments in Munc13-1-EYFP knockin mice show that Munc13-1 is rapidly and continuously exchanged at active zones (tau1 ~3 min; tau2 ~80 min), demonstrating that presynaptic active zones are highly dynamic; exchange kinetics are reduced by chronic suppression of spontaneous activity but not by proteasome inhibitors or acute stimulation. FRAP in knockin mice expressing endogenous Munc13-1-EYFP; live imaging The Journal of neuroscience : the official journal of the Society for Neuroscience High 17167095
2003 Munc13-1 is present in pancreatic islet beta cells and regulates insulin granule priming; overexpressed Munc13-1 translocates to plasma membrane in a diacylglycerol-dependent manner and greatly amplifies insulin exocytosis, an effect abolished by the DAG binding-deficient H567K mutant. Patch-clamp capacitance measurements; radioimmunoassay; GFP-fusion overexpression with DAG binding-deficient mutant The Journal of biological chemistry High 12871971
2006 Munc13-1 heterozygous knockout mice exhibit reduced glucose-stimulated insulin secretion and abnormal glucose tolerance due to a primary islet beta-cell secretory defect involving granule priming deficits; DAG binding-deficient Munc13-1(H567K) knockin shows milder effects, confirming DAG-dependent priming role. Heterozygous knockout and knockin mice; glucose tolerance tests; patch-clamp capacitance measurements in beta cells Diabetes High 16644700
2006 Munc13-1 is required for the second phase of sustained insulin release from pancreatic beta cells; Munc13-1 knockout reduces sustained release upon prolonged stimulation, and this involves DAG signaling since it is also reduced in H567K DAG-binding-deficient knockin mice. Munc13-1 knockout and knockin mice; patch-clamp exocytosis measurements in primary beta cells Cell metabolism High 16697276
2011 Munc13-1 is required for presynaptic long-term potentiation (LTP) at hippocampal mossy fiber synapses, and the interaction between RIM1α and Munc13-1 (via the RIM-binding domain) is required for this plasticity, implicating modulation of vesicle priming as the substrate for mossy fiber LTP. Acute in vivo viral expression of Munc13-1 domain constructs; electrophysiology at mossy fiber synapses; genetic epistasis The Journal of neuroscience : the official journal of the Society for Neuroscience High 21849565
2016 Homozygous loss-of-function nonsense mutation in the N-terminal domain of MUNC13-1 (truncating after residue 101) causes marked depletion of the readily releasable pool of quanta at the neuromuscular junction with normal quantal release probability, and produces a fatal syndrome of microcephaly, cortical hyperexcitability, and myasthenia; mechanistically interpreted as syntaxin 1B being consigned to a nonfunctional closed state. Exome sequencing; in vitro microelectrode studies of neuromuscular transmission; electron microscopy of neuromuscular junctions Neurology. Genetics High 27648472
2021 Two distinct membrane-binding faces of the Munc13-1 C1C2B region control neurotransmitter release: a polybasic face (K603, R769) mediates Ca2+-independent liposome bridging and is essential for synaptic vesicle priming; a DAG/Ca2+/PIP2-binding face modulates Ca2+-evoked release and short-term plasticity. Site-directed mutagenesis; in vitro liposome bridging/fusion reconstitution; electrophysiology in hippocampal cultures eLife High 34779770
2021 Munc13-1 regulates synaptic vesicle replenishment via a Ca2+-phospholipid-dependent mechanism through its C2B domain; knockin mice with mutations abolishing Ca2+-phospholipid binding show increased synaptic depression and slowed recovery, while enhanced binding has opposite effects, establishing Munc13-1 as a core vesicle priming hub adjusting SV re-supply to demand. Knockin mouse lines with C2B domain point mutations; electrophysiology at calyx of Held Neuron High 34706220
2020 NMR spectroscopy and SNARE assembly experiments show that Munc13-1 opens syntaxin-1 via interactions with the syntaxin-1 linker region (part of the closed conformation); point mutations in the linker strongly impair SNARE complex assembly and liposome fusion mediated by Munc13-1 fragments, even though direct binding of the linker to Munc13-1 is barely detectable; the syntaxin-1 SNARE motif binds Munc13-1 but disrupting this does not affect SNARE assembly. NMR spectroscopy; SNARE complex assembly assays; liposome fusion assays; mutagenesis Protein science : a publication of the Protein Society High 32086964
2022 TDP-43 represses a cryptic exon-splicing event in UNC13A; loss of TDP-43 from the nucleus in human brain, neuronal cell lines, and iPSC-derived motor neurons causes inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression; ALS/FTD risk SNPs in the intron harboring the cryptic exon increase its inclusion in the context of TDP-43 dysfunction. TDP-43 knockdown/depletion in cell lines and iPSC-derived neurons; RNA splicing assays; patient brain tissue analysis; SNP functional testing Nature High 35197626
2022 TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein; two common intronic UNC13A polymorphisms at TDP-43 binding sites potentiate cryptic exon inclusion in cultured cells and in patient brain/spinal cord tissue. TDP-43 knockdown; RNA-seq; NMD inhibition assays; patient brain and spinal cord tissue; cell-based cryptic exon reporter assays Nature High 35197628
2023 TDP-43's extreme N-terminus is important for repressing UNC13A cryptic exon inclusion; hnRNP L, hnRNP A1, and hnRNP A2B1 independently bind UNC13A RNA and repress cryptic exon inclusion in a TDP-43-independent manner; higher hnRNP L protein levels correlate with lower UNC13A cryptic RNA burden in ALS/FTD brains. TDP-43 domain deletion; RNA-binding protein knockdown; patient brain tissue correlation; RNA-immunoprecipitation PLoS biology High 36930682
2018 TNF-α impedes Fbxo45-dependent ubiquitination of Munc13-1 in spinal dorsal horn neurons, causing Munc13-1 accumulation at the presynaptic area; this accumulation increases mEPSC frequency and underlies neuropathic allodynia; knockdown of Fbxo45 in naive animals phenocopies neuropathic injury. Co-immunoprecipitation; ubiquitination assay; siRNA knockdown; behavioral allodynia testing; electrophysiology (mEPSC recording) in rat spinal cord Cell death & disease Medium 30042425
2013 Munc13-1 translocates to the plasma membrane in a Doc2B- and Ca2+-dependent manner; co-expression with Doc2B enables Ca2+-triggered Munc13-1 plasma membrane recruitment; accumulation at the membrane depends on DAG, as the DAG-binding-deficient H567K mutant shows reduced accumulation. Live-cell imaging of fluorescently tagged proteins in PC12 cells; Ca2+ stimulation; H567K mutant comparison Frontiers in endocrinology Medium 24062723
2013 Munc13-1 at the C1 domain directly binds alcohols (ethanol, butanol, octanol) with the binding site mapped to Glu-582 by photoaffinity labeling and mass spectrometry; Glu-582 mutations reduce alcohol binding; Drosophila Dunc-13 loss increases ethanol self-administration, rescued by rat Munc13-1 expression. Intrinsic fluorescence quenching; photoaffinity labeling with mass spectrometry; site-directed mutagenesis; Drosophila behavioral genetics Journal of neurochemistry Medium 23692447
2024 The Munc13-1 N-terminal region exerts autoinhibitory control over the C-terminal MUN domain: the C2A domain and CaM-binding domain each interact with the MUN domain and suppress SNARE assembly/liposome fusion activity; these inhibitory interactions are relieved by RIM2α zinc-finger domain and calmodulin, respectively. Purification of near-full-length Munc13-1 fragment; liposome fusion assays; NMR spectroscopy Journal of molecular biology High 38417672
2021 Munc13-1 self-assembles into nano-clusters on supported lipid bilayers; only clusters of ≥6 copies efficiently capture and retain synaptic vesicles; the C-terminal C2C domain is required for vesicle capture but not for clustering. Quantitative TIRF microscopy; step-wise photobleaching; reconstitution on supported lipid bilayers FEBS letters Medium 34227103
2024 Munc13-1 clusters multiple SNARE complexes at the release site to synchronize fusion events, while Munc18-1 stoichiometrically interacts with trans-SNARE complexes to enhance N-to-C terminal zippering; when both are present, they differentially access dynamic trans-SNARE complexes to regulate fusion pore properties and quantal size. Single-vesicle fusion reconstitution; single-molecule imaging; SNARE complex assembly assays Nature communications High 38755165
2025 A negatively charged polyE sequence in the Munc13-1 N-terminus (unique to Munc13-1 among Munc13 isoforms) binds the MUN domain via charge-charge interactions, inhibiting MUN activity in SNARE complex assembly; Ca2+ ions at ~40 μM compete with the polyE-MUN interaction to relieve this autoinhibition, providing a mechanism by which presynaptic Ca2+ influx activates Munc13-1. In vitro binding assays; SNARE complex assembly assays; mutagenesis (pseudophosphorylation); Ca2+ binding experiments Proceedings of the National Academy of Sciences of the United States of America High 40489622
2025 ALS-associated RBPs MATR3, FUS, and hnRNPA1 regulate UNC13A transcription by binding to and downregulating REST mRNA, thereby de-repressing UNC13A transcription; loss of any of these RBPs in cultured cells or iPSC-derived motor neurons leads to REST overexpression and reduced UNC13A, the same pattern observed in motor neurons of ALS patients. RBP knockdown in cell lines; iPSC-derived motor neurons; patient tissue analysis; RNA-binding assays The EMBO journal Medium 40707625
2024 TDP-43 depletion causes severe reduction in synaptic transmission (asynchronous network activity) largely driven by loss of UNC13A protein from cryptic exon inclusion; antisense oligonucleotides targeting the UNC13A cryptic exon rescue UNC13A protein levels and restore normal synaptic function. TDP-43 depletion in iPSC-derived neurons; MEA recordings; ASO treatment rescue experiments bioRxivpreprint Medium 38979232
2025 Germline coding or splice-site variants in UNC13A cause a neurodevelopmental syndrome; three mechanisms of pathogenicity are identified: (1) reduced synaptic strength from reduced UNC13A protein expression, (2) increased neurotransmission from UNC13A gain-of-function, and (3) impaired regulation of neurotransmission by second messenger signalling—validated in mouse hippocampal neurons and C. elegans. Variant expression in mouse hippocampal neurons; C. elegans functional assays; electrophysiology; exome sequencing of patient cohort Nature genetics High 41125872
2023 Unc13A's calmodulin-binding domain (CaM-domain) dynamically stabilizes vesicle priming at release sites; CaM-domain mutation causes constitutive stabilization, increasing baseline transmission while blocking both short-term facilitation and presynaptic homeostatic potentiation; phorbol ester treatment similarly enhances release and blocks plasticity in wild-type, and is occluded by the CaM-domain mutation. Drosophila NMJ genetics; electrophysiology; STED super-resolution microscopy; mathematical modeling Cell reports High 37243591
2019 RIM-BP2 primes synaptic vesicles at hippocampal mossy fiber synapses via recruitment and stabilization of Munc13-1 at the active zone; loss of RIM-BP2 reduces Munc13-1 at mossy fiber active zones and impairs vesicle docking/priming and release probability at this synapse type but has only mild effects at CA3-CA1 synapses. RIM-BP2 knockout mice; electrophysiology at two synapse types; immunogold electron microscopy for Munc13-1 localization eLife High 31535974

Source papers

Stage 0 corpus · 91 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature 603 10440375
2022 TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A. Nature 404 35197626
2022 TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. Nature 376 35197628
1998 Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release. Neuron 358 9697857
2009 Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nature genetics 329 19734901
2001 Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming. Neuron 324 11343654
2002 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 239 12163476
1997 Direct interaction of the rat unc-13 homologue Munc13-1 with the N terminus of syntaxin. The Journal of biological chemistry 237 8999968
2017 Synaptic weight set by Munc13-1 supramolecular assemblies. Nature neuroscience 190 29230050
2007 Munc13-1 C1 domain activation lowers the energy barrier for synaptic vesicle fusion. The Journal of neuroscience : the official journal of the Society for Neuroscience 159 17267576
2013 Dynamic control of synaptic vesicle replenishment and short-term plasticity by Ca(2+)-calmodulin-Munc13-1 signaling. Neuron 136 23770256
2005 Identification of the minimal protein domain required for priming activity of Munc13-1. Current biology : CB 110 16271475
2011 UNC13A is a modifier of survival in amyotrophic lateral sclerosis. Neurobiology of aging 108 22118904
2006 Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. PLoS biology 102 16732694
2019 Membrane bridging by Munc13-1 is crucial for neurotransmitter release. eLife 95 30816091
2003 Regulation of insulin exocytosis by Munc13-1. The Journal of biological chemistry 95 12871971
2017 Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder. The Journal of clinical investigation 94 28192369
2014 C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis. Annals of neurology 93 24931836
2006 Munc13-1 deficiency reduces insulin secretion and causes abnormal glucose tolerance. Diabetes 90 16644700
2006 Munc13-1 is required for the sustained release of insulin from pancreatic beta cells. Cell metabolism 87 16697276
2006 Binding to Rab3A-interacting molecule RIM regulates the presynaptic recruitment of Munc13-1 and ubMunc13-2. The Journal of biological chemistry 84 16704978
2009 A protein interaction node at the neurotransmitter release site: domains of Aczonin/Piccolo, Bassoon, CAST, and rim converge on the N-terminal domain of Munc13-1. The Journal of neuroscience : the official journal of the Society for Neuroscience 76 19812333
2012 UNC13A influences survival in Italian amyotrophic lateral sclerosis patients: a population-based study. Neurobiology of aging 67 22921269
2019 Munc13-1 MUN domain and Munc18-1 cooperatively chaperone SNARE assembly through a tetrameric complex. Proceedings of the National Academy of Sciences of the United States of America 62 31888993
2006 Molecular dynamics of a presynaptic active zone protein studied in Munc13-1-enhanced yellow fluorescent protein knock-in mutant mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 62 17167095
2016 Loss of MUNC13-1 function causes microcephaly, cortical hyperexcitability, and fatal myasthenia. Neurology. Genetics 55 27648472
2007 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 55 17639022
2007 Potentiation of exocytosis by phospholipase C-coupled G-protein-coupled receptors requires the priming protein Munc13-1. The Journal of neuroscience : the official journal of the Society for Neuroscience 54 17202488
2005 Intramolecular occlusion of the diacylglycerol-binding site in the C1 domain of munc13-1. Biochemistry 50 15667202
2024 Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer's disease. Acta neuropathologica 46 38175301
2023 TDP-43 and other hnRNPs regulate cryptic exon inclusion of a key ALS/FTD risk gene, UNC13A. PLoS biology 44 36930682
2019 RIM-BP2 primes synaptic vesicles via recruitment of Munc13-1 at hippocampal mossy fiber synapses. eLife 44 31535974
2023 UNC13A in amyotrophic lateral sclerosis: from genetic association to therapeutic target. Journal of neurology, neurosurgery, and psychiatry 40 36737245
2013 β-Adrenergic receptors activate exchange protein directly activated by cAMP (Epac), translocate Munc13-1, and enhance the Rab3A-RIM1α interaction to potentiate glutamate release at cerebrocortical nerve terminals. The Journal of biological chemistry 40 24036110
2021 Munc13-1 is a Ca2+-phospholipid-dependent vesicle priming hub that shapes synaptic short-term plasticity and enables sustained neurotransmission. Neuron 39 34706220
2018 UNC13A polymorphism contributes to frontotemporal disease in sporadic amyotrophic lateral sclerosis. Neurobiology of aging 36 30368160
2021 Control of neurotransmitter release by two distinct membrane-binding faces of the Munc13-1 C1C2B region. eLife 35 34779770
2011 Munc13-1 is required for presynaptic long-term potentiation. The Journal of neuroscience : the official journal of the Society for Neuroscience 35 21849565
2015 UNC13A confers risk for sporadic ALS and influences survival in a Spanish cohort. Journal of neurology 33 26162714
2020 The Distinct Traits of the UNC13A Polymorphism in Amyotrophic Lateral Sclerosis. Annals of neurology 31 32627229
2004 Munc13-1-mediated vesicle priming contributes to secretory amyloid precursor protein processing. The Journal of biological chemistry 31 15123597
2011 Involvement of Rab3A in vesicle priming during exocytosis: interaction with Munc13-1 and Munc18-1. Traffic (Copenhagen, Denmark) 29 21689256
2019 UNC13A variant rs12608932 is associated with increased risk of amyotrophic lateral sclerosis and reduced patient survival: a meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 28 31201598
2013 The pre-synaptic Munc13-1 binds alcohol and modulates alcohol self-administration in Drosophila. Journal of neurochemistry 28 23692447
2016 Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis & frontotemporal degeneration 23 27584932
2020 Re-examining how Munc13-1 facilitates opening of syntaxin-1. Protein science : a publication of the Protein Society 22 32086964
2024 Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs. bioRxiv : the preprint server for biology 20 38979232
2022 Neuronal SNARE complex assembly guided by Munc18-1 and Munc13-1. FEBS open bio 20 35278279
2021 Vesicle capture by membrane-bound Munc13-1 requires self-assembly into discrete clusters. FEBS letters 20 34227103
2001 The synaptic vesicle priming protein Munc13-1 is absent from tonically active ribbon synapses of the rat retina. Brain research 20 11259787
2022 Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial. Trials 18 36471413
2018 Spinal TNF-α impedes Fbxo45-dependent Munc13-1 ubiquitination to mediate neuropathic allodynia in rats. Cell death & disease 18 30042425
2013 Munc13-1 Translocates to the Plasma Membrane in a Doc2B- and Calcium-Dependent Manner. Frontiers in endocrinology 17 24062723
2007 Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoproteins Munc18 or NSF as phospho-state-sensitive modulators of phorbol/PKC-activated Alzheimer APP ectodomain shedding. Molecular neurodegeneration 15 18067682
2023 Unc13A dynamically stabilizes vesicle priming at synaptic release sites for short-term facilitation and homeostatic potentiation. Cell reports 14 37243591
2013 Calcium-dependent activator protein for secretion 1 (CAPS1) binds to syntaxin-1 in a distinct mode from Munc13-1. The Journal of biological chemistry 14 23801330
2023 Association of the risk factor UNC13A with survival and upper motor neuron involvement in amyotrophic lateral sclerosis. Frontiers in aging neuroscience 13 36819716
2022 Interdomain Dynamics via Paramagnetic NMR on the Highly Flexible Complex Calmodulin/Munc13-1. Journal of the American Chemical Society 11 36082939
2024 Differential SNARE chaperoning by Munc13-1 and Munc18-1 dictates fusion pore fate at the release site. Nature communications 10 38755165
2017 Resveratrol inhibits phorbol ester-induced membrane translocation of presynaptic Munc13-1. Biochimica et biophysica acta. General subjects 9 28713022
2022 Clinical and Metabolic Signature of UNC13A rs12608932 Variant in Amyotrophic Lateral Sclerosis. Neurology. Genetics 8 36313067
2024 Loss of postsynaptic NMDARs drives nanoscale reorganization of Munc13-1 and PSD-95. bioRxiv : the preprint server for biology 6 38260705
2022 Phorbolester-activated Munc13-1 and ubMunc13-2 exert opposing effects on dense-core vesicle secretion. eLife 6 36214779
2020 Effect of ethanol on Munc13-1 C1 in Membrane: A Molecular Dynamics Simulation Study. Alcoholism, clinical and experimental research 6 32424866
2018 Critical Role of Trp-588 of Presynaptic Munc13-1 for Ligand Binding and Membrane Translocation. Biochemistry 6 29244485
2024 Control of Munc13-1 Activity by Autoinhibitory Interactions Involving the Variable N-terminal Region. Journal of molecular biology 5 38417672
2024 Quantification of serum TDP-43 and neurofilament light chain in patients with amyotrophic lateral sclerosis stratified by UNC13A genotype. Journal of the neurological sciences 5 39241471
2020 The Unc13A isoform is important for phasic release and olfactory memory formation at mushroom body synapses. Journal of neurogenetics 5 31980003
2021 Probing the Diacylglycerol Binding Site of Presynaptic Munc13-1. Biochemistry 4 33818064
2023 Correction: TDP-43 and other hnRNPs regulate cryptic exon inclusion of a key ALS/FTD risk gene, UNC13A. PLoS biology 3 37451236
2022 Differential Expression of Presynaptic Munc13-1 and Munc13-2 in Mouse Hippocampus Following Ethanol Drinking. Neuroscience 3 35167938
2022 Homozygous UNC13A Variant in an Infant With Congenital Encephalopathy and Severe Neuromuscular Phenotype: A Case Report With Detailed Central Nervous System Neuropathologic Findings. Cureus 3 36447687
2019 MUNC13-1 heterozygosity does not alter voluntary ethanol consumption or sensitivity in mice. Alcohol (Fayetteville, N.Y.) 3 31265903
2025 Endogenous SNAP-Tagging of Munc13‑1 for Monitoring Synapse Nanoarchitecture. JACS Au 2 40575326
2025 Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nature genetics 2 41125872
2021 Molecular dynamics simulation studies on binding of activator and inhibitor to Munc13-1 C1 in the presence of membrane. Journal of biomolecular structure & dynamics 2 34779746
2013 Reduced expression of Munc13-1 in human and porcine diabetic peripheral nerve. Acta histochemica 2 23830992
2008 Characterization of Munc13-1 and insulin secretion during pancreatic development in rats. Journal of endocrinological investigation 2 18787382
2026 Munc13-1 couples DAG and Ca2+ signaling to dynamic vesicle priming, synaptic short-term plasticity, and posttetanic potentiation. Science advances 1 41686904
2017 Inhibitory role of Munc13-1 in antigen-induced mast cell degranulation. Biomedical research (Tokyo, Japan) 1 29225210
2007 Expression, purification and characterization of critical domains of Munc13-1. Acta biochimica et biophysica Sinica 1 17687497
2026 Homozygosity for the C allele at UNC13A rs12608932 seems to compromise cognition in ALS independently of the cognitive domains. Amyotrophic lateral sclerosis & frontotemporal degeneration 0 41481541
2026 Ca2+-phospholipid-dependent regulation of Munc13-1 is essential for post-tetanic potentiation at mossy fiber synapses and supports working memory. Cell reports 0 41719128
2025 Characterization of human healthy i3 lower motor neurons exposed to CSF from ALS patients stratified by UNC13A and C9ORF72 genotype. Journal of the neurological sciences 0 40250093
2025 A specific negatively charged sequence confers intramolecular regulation on Munc13-1 function in synaptic exocytosis. Proceedings of the National Academy of Sciences of the United States of America 0 40489622
2025 ALS-associated RNA-binding proteins promote UNC13A transcription through REST downregulation. The EMBO journal 0 40707625
2025 U7 small nuclear RNA splice-switching therapeutics for STMN2 and UNC13A in Amyotrophic Lateral Sclerosis. bioRxiv : the preprint server for biology 0 41394711
2025 Dual-targeting snRNA gene therapy rescues STMN2 and UNC13A splicing in TDP-43 proteinopathies. bioRxiv : the preprint server for biology 0 41573891
2024 Control of Munc13-1 Activity by Autoinhibitory Interactions Involving the Variable N-terminal Region. bioRxiv : the preprint server for biology 0 38328168
2023 Activation of Munc13-1 by Diacylglycerol (DAG)-Lactones. Biochemistry 0 37651159
2023 Interaction of the C9orf72-Amyotrophic Lateral Sclerosis-Related Proline-Arginine Dipeptide Repeat Protein with the RNA-Binding Protein NOVA1 Causes Decreased Expression of UNC13A Due to Enhanced Inclusion of Cryptic Exons, Which Is Reversed by Betulin Treatment. Cells 0 37887320