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1.
Trends Mol Med ; 28(12): 1009-1011, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36336609
2.
Trends Mol Med ; 28(5): 345-346, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35410766
5.
Trends Endocrinol Metab ; 32(8): 531-532, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34210608
6.
Trends Mol Med ; 27(1): 1, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33308981
7.
Trends Mol Med ; 26(9): 797-798, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32857967
9.
Elife ; 82019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31535974

RESUMO

All synapses require fusion-competent vesicles and coordinated Ca2+-secretion coupling for neurotransmission, yet functional and anatomical properties are diverse across different synapse types. We show that the presynaptic protein RIM-BP2 has diversified functions in neurotransmitter release at different central murine synapses and thus contributes to synaptic diversity. At hippocampal pyramidal CA3-CA1 synapses, RIM-BP2 loss has a mild effect on neurotransmitter release, by only regulating Ca2+-secretion coupling. However, at hippocampal mossy fiber synapses, RIM-BP2 has a substantial impact on neurotransmitter release by promoting vesicle docking/priming and vesicular release probability via stabilization of Munc13-1 at the active zone. We suggest that differences in the active zone organization may dictate the role a protein plays in synaptic transmission and that differences in active zone architecture is a major determinant factor in the functional diversity of synapses.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fibras Musgosas Hipocampais/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Vesículas Sinápticas/metabolismo , Animais , Camundongos , Neurotransmissores/metabolismo
10.
Nat Commun ; 10(1): 486, 2019 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-30700723

RESUMO

Drebrin (DBN) regulates cytoskeletal functions during neuronal development, and is thought to contribute to structural and functional synaptic changes associated with aging and Alzheimer's disease. Here we show that DBN coordinates stress signalling with cytoskeletal dynamics, via a mechanism involving kinase ataxia-telangiectasia mutated (ATM). An excess of reactive oxygen species (ROS) stimulates ATM-dependent phosphorylation of DBN at serine-647, which enhances protein stability and accounts for improved stress resilience in dendritic spines. We generated a humanized DBN Caenorhabditis elegans model and show that a phospho-DBN mutant disrupts the protective ATM effect on lifespan under sustained oxidative stress. Our data indicate a master regulatory function of ATM-DBN in integrating cytosolic stress-induced signalling with the dynamics of actin remodelling to provide protection from synapse dysfunction and ROS-triggered reduced lifespan. They further suggest that DBN protein abundance governs actin filament stability to contribute to the consequences of oxidative stress in physiological and pathological conditions.


Assuntos
Actinas/metabolismo , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Estresse Oxidativo , Actinas/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Motivos de Aminoácidos , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Caenorhabditis elegans , Células Cultivadas , Espinhas Dendríticas/genética , Espinhas Dendríticas/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuropeptídeos/genética , Fosforilação , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
11.
Trends Mol Med ; 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30737011

RESUMO

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

12.
Sci Rep ; 7: 42652, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28198431

RESUMO

The dynamic regulation of the actin cytoskeleton plays a key role in controlling the structure and function of synapses. It is vital for activity-dependent modulation of synaptic transmission and long-term changes in synaptic morphology associated with memory consolidation. Several regulators of actin dynamics at the synapse have been identified, of which a salient one is the postsynaptic actin stabilising protein Drebrin (DBN). It has been suggested that DBN modulates neurotransmission and changes in dendritic spine morphology associated with synaptic plasticity. Given that a decrease in DBN levels is correlated with cognitive deficits associated with ageing and dementia, it was hypothesised that DBN protein abundance instructs the integrity and function of synapses. We created a novel DBN deficient mouse line. Analysis of gross brain and neuronal morphology revealed no phenotype in the absence of DBN. Electrophysiological recordings in acute hippocampal slices and primary hippocampal neuronal cultures showed that basal synaptic transmission, and both long-term and homeostatic synaptic plasticity were unchanged, suggesting that loss of DBN is not sufficient in inducing synapse dysfunction. We propose that the overall lack of changes in synaptic function and plasticity in DBN deficient mice may indicate robust compensatory mechanisms that safeguard cytoskeleton dynamics at the synapse.

13.
Proc Natl Acad Sci U S A ; 113(41): 11615-11620, 2016 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-27671655

RESUMO

The tight spatial coupling of synaptic vesicles and voltage-gated Ca2+ channels (CaVs) ensures efficient action potential-triggered neurotransmitter release from presynaptic active zones (AZs). Rab-interacting molecule-binding proteins (RIM-BPs) interact with Ca2+ channels and via RIM with other components of the release machinery. Although human RIM-BPs have been implicated in autism spectrum disorders, little is known about the role of mammalian RIM-BPs in synaptic transmission. We investigated RIM-BP2-deficient murine hippocampal neurons in cultures and slices. Short-term facilitation is significantly enhanced in both model systems. Detailed analysis in culture revealed a reduction in initial release probability, which presumably underlies the increased short-term facilitation. Superresolution microscopy revealed an impairment in CaV2.1 clustering at AZs, which likely alters Ca2+ nanodomains at release sites and thereby affects release probability. Additional deletion of RIM-BP1 does not exacerbate the phenotype, indicating that RIM-BP2 is the dominating RIM-BP isoform at these synapses.


Assuntos
Canais de Cálcio/metabolismo , Hipocampo/metabolismo , Sinapses/metabolismo , Potenciais de Ação , Animais , Cálcio/metabolismo , Células Cultivadas , Fenômenos Eletrofisiológicos , Feminino , Deleção de Genes , Expressão Gênica , Marcação de Genes , Loci Gênicos , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Fenótipo , Transporte Proteico , Transmissão Sináptica/genética , Vesículas Sinápticas/metabolismo
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