RIM-BP2 primes synaptic vesicles <i>via</i> recruitment of Munc13-1 at hippocampal mossy fiber synapses

Brockmann, Marisa M; Maglione, Marta; Willmes, Claudia; Stumpf, Alexander; Bouazza, Boris A; Moreno-Velasquez, Laura; Grauel, M. Katharina; Beed, Prateep; Sigrist, Stephan J.; Rosenmund, Christian; Schmitz, Dietmar

doi:10.1101/469494

Cited by 21 publications

(32 citation statements)

References 37 publications

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“…At the cellular level, K-Ca 2+ channel dysfunction leads to uncoordinated firing patterns in Purkinje cells, which is expected to alter the fidelity and reliability of information transfer to downstream targets in the deep cerebellar nuclei (45). This phenotype is identical to that observed upon genetic removal of RIMBPs from other central synapses (43). Importantly, evidence from human genetic studies supports the role of perturbed presynaptic neurotransmitter release in the pathogenesis of hyperkinetic movement disorders.…”

Section: Discussionsupporting

confidence: 66%

“…Therefore, mechanistically, RIMBP1 variants can influence synaptic function by altering the clustering of release-relevant presynaptic VGCCs. Loss-of-function variants are expected to reduce the density of active zone VGCCs, as observed in central synapses of mice lacking RIMBPs (18,19,28,43). Conversely, the missense variant found in family C (p.Gly1806Ser) increased the extent of transmitter in response to action potentials.…”

Section: Discussionmentioning

confidence: 99%

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Bi-allelic variants inTSPOAP1, encoding the active zone protein RIMBP1, cause autosomal recessive dystonia

Mencacci

Brockmann

Dai

et al. 2020

Preprint

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Dystonia is a debilitating hyperkinetic movement disorder, frequently transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense and missense variants in TSPOAP1, encoding the active zone RIM-binding protein 1 (RIMBP1), as a novel genetic cause of autosomal recessive dystonia in seven subjects from three unrelated families. Subjects carrying loss-of-function variants presented with juvenileonset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between presynaptic RIMBP1 dysfunction and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Bi-allelic variants inTSPOAP1, encoding the active zone protein RIMBP1, cause autosomal recessive dystonia

Mencacci

Brockmann

Dai

et al. 2020

Preprint

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“…RIM and RBP are established targets for multiple forms of presynaptic plasticity in several synapse types and species 5, 16, 17, 62, 73 . Here we additionally identified a critical role for Unc13A (Fig.…”

Section: Discussionmentioning

confidence: 99%

Rapid active zone remodeling consolidates presynaptic potentiation

Boehme

McCarthy

Grasskamp

et al. 2018

Preprint

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1 Synaptic transmission is mediated by neurotransmitter release at presynaptic active zones (AZs) 2 followed by postsynaptic neurotransmitter detection. Plastic changes in transmission maintain 3 functionality during perturbations and enable memory formation. Postsynaptic plasticity targets 4 neurotransmitter receptors, but presynaptic plasticity mechanisms directly regulating the 5 neurotransmitter release apparatus remain largely enigmatic. Here we describe that AZs consist 6 of nano-modular release site units and identify a molecular sequence adding more modules 7 within minutes of plasticity induction. This requires cognate transport machinery and a discrete 8 subset of AZ scaffold proteins. Structural remodeling is not required for the immediate 9 potentiation of neurotransmitter release, but rather necessary to sustain this potentiation over 10 longer timescales. Finally, mutations in Unc13 that disrupt homeostatic plasticity at the 11 neuromuscular junction also impair shot-term memory when central neurons are targeted, 12 suggesting that both forms of plasticity operate via Unc13. Together, while immediate synaptic 13 potentiation capitalizes on available material, it triggers the coincident incorporation of modular 14 release sites to consolidate stable synapse function. 16Neurotransmitter-laden synaptic vesicles (SVs) release their content at presynaptic active zones 17 (AZs) in response to Ca 2+ influx through voltage gated channels that respond to action-potential 18 (AP) depolarization. Neurotransmitter binding to postsynaptic receptors subsequently leads to 19 their activation for synaptic transmission. Modulation of transmission strength is called synaptic 20 plasticity. Long-term forms of synaptic plasticity are major cellular substrates for learning, 21 memory, and behavioral adaptation 1, 2 . Mechanisms of long-term synaptic plasticity modify the 22 structure and function of the presynaptic terminal and/or the postsynaptic apparatus. AZs are 23 covered by complex scaffolds composed of a conserved set of extended structural proteins. 24 ELKS/Bruchpilot (BRP), RIM, and RIM-binding protein (RBP) functionally organize the 25 coupling between Ca 2+ -channels and release machinery by immobilizing the critical (M)Unc13 26 release factors in clusters close to presynaptic Ca 2+ -channels and thus generate SV release sites, 27 at both mammalian and Drosophila synapses 3-12 . Whether and how discrete AZ release sites and 28 the associated release machinery are reorganized during plastic changes remains unknown. 29 One crucial form of presynaptic plasticity is the homeostatic control of neurotransmitter 30 release. This process, referred to as presynaptic homeostatic potentiation (PHP), is observed in 31 organisms ranging from invertebrates to humans, but is perhaps best illustrated at the larval 32 neuromuscular junction (NMJ) of Drosophila melanogaster 13, 14 . Here, PHP requires the core 33 AZ-scaffolding proteins RIM, RBP and Fife 15-17 and physiologically coincides with the 34 upregulat...

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“…In mammals, while RIMBP2 is associated with presynaptic functions [ 14 , 55 , 56 ], RIMBP3 proteins seem to have a role in microtubule organization, especially in spermatozoa [ 17 , 57 ]. Possibly, these different biological roles can be associated with their divergent domain architecture ( Figure S1 ).…”

Section: Discussionmentioning

confidence: 99%

Rimbp, a New Marker for the Nervous System of the Tunicate Ciona robusta

Coppola

Olivo

D’Aniello

et al. 2020

Genes

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Establishment of presynaptic mechanisms by proteins that regulate neurotransmitter release in the presynaptic active zone is considered a fundamental step in animal evolution. Rab3 interacting molecule-binding proteins (Rimbps) are crucial components of the presynaptic active zone and key players in calcium homeostasis. Although Rimbp involvement in these dynamics has been described in distantly related models such as fly and human, the role of this family in most invertebrates remains obscure. To fill this gap, we defined the evolutionary history of Rimbp family in animals, from sponges to mammals. We report, for the first time, the expression of the two isoforms of the unique Rimbp family member in Ciona robusta in distinct domains of the larval nervous system. We identify intronic enhancers that are able to drive expression in different nervous system territories partially corresponding to Rimbp endogenous expression. The analysis of gene expression patterns and the identification of regulatory elements of Rimbp will positively impact our understanding of this family of genes in the context of Ciona embryogenesis.

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RIM-BP2 primes synaptic vesicles via recruitment of Munc13-1 at hippocampal mossy fiber synapses

Cited by 21 publications

References 37 publications

Bi-allelic variants inTSPOAP1, encoding the active zone protein RIMBP1, cause autosomal recessive dystonia

Bi-allelic variants inTSPOAP1, encoding the active zone protein RIMBP1, cause autosomal recessive dystonia

Rapid active zone remodeling consolidates presynaptic potentiation

Rimbp, a New Marker for the Nervous System of the Tunicate Ciona robusta

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