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1.
Cell ; 171(5): 1151-1164.e16, 2017 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-29056337

RESUMO

In mammals, the environment plays a critical role in promoting the final steps in neuronal development during the early postnatal period. While epigenetic factors are thought to contribute to this process, the underlying molecular mechanisms remain poorly understood. Here, we show that in the brain during early life, the DNA methyltransferase DNMT3A transiently binds across transcribed regions of lowly expressed genes, and its binding specifies the pattern of DNA methylation at CA sequences (mCA) within these genes. We find that DNMT3A occupancy and mCA deposition within the transcribed regions of genes is negatively regulated by gene transcription and may be modified by early-life experience. Once deposited, mCA is bound by the methyl-DNA-binding protein MECP2 and functions in a rheostat-like manner to fine-tune the cell-type-specific transcription of genes that are critical for brain function.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , Epigênese Genética , Neurônios/metabolismo , Animais , Encéfalo/citologia , Encéfalo/metabolismo , DNA Metiltransferase 3A , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Proteína 2 de Ligação a Metil-CpG , Camundongos , Transcrição Gênica , Ativação Transcricional
2.
Annu Rev Cell Dev Biol ; 27: 465-91, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21740229

RESUMO

Cyclin-dependent kinase 5 (Cdk5) is a multifaceted serine/threonine kinase protein with important roles in the nervous system. Two related proteins, p35 and p39, activate Cdk5 upon direct binding. Over the past decade, Cdk5 activity has been demonstrated to regulate many events during brain development, including neuronal migration as well as axon and dendrite development. Recent evidence also suggests a pivotal role for Cdk5 in synaptic plasticity, behavior, and cognition. Dysfunction of Cdk5 has been implicated in a number of neurological disorders and neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Niemann-Pick type C disease, and ischemia. Hyperactivation of Cdk5 due to the conversion of p35 to p25 by the calcium-dependent protease calpain during neurotoxicity also contributes to the pathological state. This review surveys recent literature surrounding Cdk5 in synaptic plasticity and homeostasis, with particular emphasis on Cdk5 kinase activity under neurodegenerative conditions.


Assuntos
Encéfalo/enzimologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Quinase 5 Dependente de Ciclina/metabolismo , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Animais , Encéfalo/anatomia & histologia , Movimento Celular/fisiologia , Quinase 5 Dependente de Ciclina/genética , Epigênese Genética , Homeostase , Humanos , Aprendizagem/fisiologia , Memória/fisiologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuritos/metabolismo , Plasticidade Neuronal/fisiologia , Transmissão Sináptica/fisiologia , Vesículas Sinápticas/metabolismo
3.
Proc Natl Acad Sci U S A ; 118(6)2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33526652

RESUMO

Identifying molecular mediators of neural circuit development and/or function that contribute to circuit dysfunction when aberrantly reengaged in neurological disorders is of high importance. The role of the TWEAK/Fn14 pathway, which was recently reported to be a microglial/neuronal axis mediating synaptic refinement in experience-dependent visual development, has not been explored in synaptic function within the mature central nervous system. By combining electrophysiological and phosphoproteomic approaches, we show that TWEAK acutely dampens basal synaptic transmission and plasticity through neuronal Fn14 and impacts the phosphorylation state of pre- and postsynaptic proteins in adult mouse hippocampal slices. Importantly, this is relevant in two models featuring synaptic deficits. Blocking TWEAK/Fn14 signaling augments synaptic function in hippocampal slices from amyloid-beta-overexpressing mice. After stroke, genetic or pharmacological inhibition of TWEAK/Fn14 signaling augments basal synaptic transmission and normalizes plasticity. Our data support a glial/neuronal axis that critically modifies synaptic physiology and pathophysiology in different contexts in the mature brain and may be a therapeutic target for improving neurophysiological outcomes.


Assuntos
Degeneração Neural/metabolismo , Transdução de Sinais , Acidente Vascular Cerebral/metabolismo , Sinapses/metabolismo , Receptor de TWEAK/metabolismo , Animais , Citocina TWEAK/metabolismo , Modelos Animais de Doenças , Feminino , Hipocampo/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Degeneração Neural/fisiopatologia , Plasticidade Neuronal/fisiologia , Terminações Pré-Sinápticas/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Transmissão Sináptica/fisiologia
4.
J Neurosci ; 37(36): 8655-8666, 2017 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-28878098

RESUMO

Diverse molecular mechanisms regulate synaptic composition and function in the mammalian nervous system. The multifunctional protein arginine methyltransferase 8 (PRMT8) possesses both methyltransferase and phospholipase activities. Here we examine the role of this neuron-specific protein in hippocampal plasticity and cognitive function. PRMT8 protein localizes to synaptic sites, and conditional whole-brain Prmt8 deletion results in altered levels of multiple synaptic proteins in the hippocampus, using both male and female mice. Interestingly, these altered protein levels are due to post-transcriptional mechanisms as the corresponding mRNA levels are unaffected. Strikingly, electrophysiological recordings from hippocampal slices of mice lacking PRMT8 reveal multiple defects in excitatory synaptic function and plasticity. Furthermore, behavioral analyses show that PRMT8 conditional knock-out mice exhibit impaired hippocampal-dependent fear learning. Together, these findings establish PRMT8 as an important component of the molecular machinery required for hippocampal neuronal function.SIGNIFICANCE STATEMENT Numerous molecular processes are critically required for normal brain function. Here we use mice lacking protein arginine methyltransferase 8 (PRMT8) in the brain to examine how loss of this protein affects the structure and function of neurons in the hippocampus. We find that PRMT8 localizes to the sites of communication between neurons. Hippocampal neurons from mice lacking PRMT8 have no detectable structural differences compared with controls; however, multiple aspects of their function are altered. Consistently, we find that mice lacking PRMT8 also exhibit reduced hippocampus-dependent memory. Together, our findings establish important roles for PRMT8 in regulating neuron function and cognition in the mammalian brain.


Assuntos
Hipocampo/fisiopatologia , Transtornos da Memória/fisiopatologia , Transtornos Mentais/fisiopatologia , Proteína-Arginina N-Metiltransferases/metabolismo , Sinapses/metabolismo , Transmissão Sináptica , Animais , Feminino , Hipocampo/patologia , Masculino , Transtornos da Memória/complicações , Transtornos da Memória/patologia , Transtornos Mentais/complicações , Transtornos Mentais/patologia , Camundongos , Camundongos Knockout , Plasticidade Neuronal , Proteína-Arginina N-Metiltransferases/genética , Sinapses/patologia
5.
Nature ; 483(7388): 222-6, 2012 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-22388814

RESUMO

Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer's disease. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer's-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer's disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.


Assuntos
Encéfalo/fisiopatologia , Epigênese Genética , Histona Desacetilase 2/genética , Transtornos da Memória/genética , Transtornos da Memória/fisiopatologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/fisiopatologia , Acetilação/efeitos dos fármacos , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Epigênese Genética/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Histona Desacetilase 2/deficiência , Histona Desacetilase 2/metabolismo , Histonas/metabolismo , Humanos , Peróxido de Hidrogênio/toxicidade , Transtornos da Memória/complicações , Camundongos , Doenças Neurodegenerativas/complicações , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/genética , Fragmentos de Peptídeos/toxicidade , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , RNA Polimerase II/metabolismo , Receptores de Glucocorticoides/metabolismo
6.
Cereb Cortex ; 26(7): 2937-51, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26088971

RESUMO

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase implicated in synaptic plasticity, behavior, and cognition, yet its synaptic function remains poorly understood. Here, we report that physiological Cdk5 signaling in rat hippocampal CA1 neurons regulates homeostatic synaptic transmission using an unexpectedly rapid mechanism that is different from all known slow homeostatic regulators, such as beta amyloid (Aß) and activity-regulated cytoskeleton-associated protein (Arc, aka Arg3.1). Interestingly, overproduction of the potent Cdk5 activator p25 reduces synapse density, and dynamically regulates synaptic size by suppressing or enhancing Aß/Arc production. Moreover, chronic overproduction of p25, seen in Alzheimer's patients, induces initially concurrent reduction in synapse density and increase in synaptic size characteristic of the early Alzheimer-like pathology, and later persistent synapse elimination in intact brains. These results identify Cdk5 as the regulator of a novel rapid form of homeostasis at central synapses and p25 as the first molecule capable of initiating the early Alzheimer's synaptic pathology.


Assuntos
Região CA1 Hipocampal/enzimologia , Região CA1 Hipocampal/patologia , Quinase 5 Dependente de Ciclina/metabolismo , Homeostase/fisiologia , Sinapses/enzimologia , Sinapses/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Células Cultivadas , Quinase 5 Dependente de Ciclina/genética , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Microscopia Eletrônica , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/fisiologia , Técnicas de Patch-Clamp , Fosfotransferases/genética , Fosfotransferases/metabolismo , Ratos , Ratos Transgênicos , Técnicas de Cultura de Tecidos
7.
J Neurosci ; 35(6): 2372-83, 2015 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-25673832

RESUMO

Perturbations in fast-spiking parvalbumin (PV) interneurons are hypothesized to be a major component of various neuropsychiatric disorders; however, the mechanisms regulating PV interneurons remain mostly unknown. Recently, cyclin-dependent kinase 5 (Cdk5) has been shown to function as a major regulator of synaptic plasticity. Here, we demonstrate that genetic ablation of Cdk5 in PV interneurons in mouse brain leads to an increase in GABAergic neurotransmission and impaired synaptic plasticity. PVCre;fCdk5 mice display a range of behavioral abnormalities, including decreased anxiety and memory impairment. Our results reveal a central role of Cdk5 expressed in PV interneurons in gating inhibitory neurotransmission and underscore the importance of such regulation during behavioral tasks. Our findings suggest that Cdk5 can be considered a promising therapeutic target in a variety of conditions attributed to inhibitory interneuronal dysfunction, such as epilepsy, anxiety disorders, and schizophrenia.


Assuntos
Ansiedade/psicologia , Quinase 5 Dependente de Ciclina/genética , Inibição Psicológica , Interneurônios/metabolismo , Transtornos da Memória/psicologia , Parvalbuminas/metabolismo , Animais , Ansiedade/genética , Comportamento Animal/fisiologia , Interneurônios/enzimologia , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/genética , Atividade Motora/fisiologia , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia , Vesículas Sinápticas/ultraestrutura , Ácido gama-Aminobutírico/metabolismo
8.
J Neurosci ; 35(15): 6038-50, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25878277

RESUMO

Mechanisms underlying motor neuron degeneration in spinal muscular atrophy (SMA), the leading inherited cause of infant mortality, remain largely unknown. Many studies have established the importance of hyperphosphorylation of the microtubule-associated protein tau in various neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. However, tau phosphorylation in SMA pathogenesis has yet to be investigated. Here we show that tau phosphorylation on serine 202 (S202) and threonine 205 (T205) is increased significantly in SMA motor neurons using two SMA mouse models and human SMA patient spinal cord samples. Interestingly, phosphorylated tau does not form aggregates in motor neurons or neuromuscular junctions (NMJs), even at late stages of SMA disease, distinguishing it from other tauopathies. Hyperphosphorylation of tau on S202 and T205 is mediated by cyclin-dependent kinase 5 (Cdk5) in SMA disease condition, because tau phosphorylation at these sites is significantly reduced in Cdk5 knock-out mice; genetic knock-out of Cdk5 activating subunit p35 in an SMA mouse model also leads to reduced tau phosphorylation on S202 and T205 in the SMA;p35(-/-) compound mutant mice. In addition, expression of the phosphorylation-deficient tauS202A,T205A mutant alleviates motor neuron defects in a zebrafish SMA model in vivo and mouse motor neuron degeneration in culture, whereas expression of phosphorylation-mimetic tauS202E,T205E promotes motor neuron defects. More importantly, genetic knock-out of tau in SMA mice rescues synapse stripping on motor neurons, NMJ denervation, and motor neuron degeneration in vivo. Altogether, our findings suggest a novel mechanism for SMA pathogenesis in which hyperphosphorylation of non-aggregating tau by Cdk5 contributes to motor neuron degeneration.


Assuntos
Quinase 5 Dependente de Ciclina/metabolismo , Neurônios Motores/patologia , Atrofia Muscular Espinal , Degeneração Neural/etiologia , Medula Espinal/patologia , Proteínas tau/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Imunoprecipitação , Lactente , Recém-Nascido , Masculino , Camundongos , Camundongos Transgênicos , Neurônios Motores/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular Espinal/complicações , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patologia , Proteínas do Tecido Nervoso/metabolismo , Junção Neuromuscular/metabolismo , Junção Neuromuscular/patologia , Proteínas Nucleares/metabolismo , Oligodesoxirribonucleotídeos Antissenso/farmacologia , Fosforilação , Proteínas Repressoras/metabolismo , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo , Peixe-Zebra , Proteínas tau/deficiência , Proteínas tau/genética
9.
Nature ; 466(7310): 1105-9, 2010 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-20622856

RESUMO

The NAD-dependent deacetylase Sir2 was initially identified as a mediator of replicative lifespan in budding yeast and was subsequently shown to modulate longevity in worms and flies. Its mammalian homologue, SIRT1, seems to have evolved complex systemic roles in cardiac function, DNA repair and genomic stability. Recent studies suggest a functional relevance of SIRT1 in normal brain physiology and neurological disorders. However, it is unknown if SIRT1 has a role in higher-order brain functions. We report that SIRT1 modulates synaptic plasticity and memory formation via a microRNA-mediated mechanism. Activation of SIRT1 enhances, whereas its loss-of-function impairs, synaptic plasticity. Surprisingly, these effects were mediated via post-transcriptional regulation of cAMP response binding protein (CREB) expression by a brain-specific microRNA, miR-134. SIRT1 normally functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1, and unchecked miR-134 expression following SIRT1 deficiency results in the downregulated expression of CREB and brain-derived neurotrophic factor (BDNF), thereby impairing synaptic plasticity. These findings demonstrate a new role for SIRT1 in cognition and a previously unknown microRNA-based mechanism by which SIRT1 regulates these processes. Furthermore, these results describe a separate branch of SIRT1 signalling, in which SIRT1 has a direct role in regulating normal brain function in a manner that is disparate from its cell survival functions, demonstrating its value as a potential therapeutic target for the treatment of central nervous system disorders.


Assuntos
Memória/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismo , Plasticidade Neuronal/genética , Sirtuína 1/genética , Sirtuína 1/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Sinapses Elétricas/genética , Sinapses Elétricas/patologia , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Potenciação de Longa Duração/genética , Masculino , Transtornos da Memória/genética , Transtornos da Memória/fisiopatologia , Camundongos , Ligação Proteica , Deleção de Sequência
10.
Neurobiol Learn Mem ; 105: 54-62, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23850563

RESUMO

Cyclin-dependent kinase 5 (Cdk5) is associated with synaptic plasticity and cognitive function. Previous reports have demonstrated that Cdk5 is necessary for memory formation, although others have reported Cdk5 conditional knockout mouse models exhibiting enhanced learning and memory. Furthermore, how Cdk5 acts in specific cell populations to affect behavior and cognitive outcomes remains unclear. Here we conduct a behavioral characterization of a forebrain-specific Cdk5 conditional knockout mouse model under the αCaMKII promoter, in which Cdk5 is ablated in excitatory pyramidal neurons of the forebrain. The Cdk5 conditional knockouts exhibit hyperactivity in the open field, reduced anxiety, and reduced behavioral despair. Moreover, the Cdk5 conditional knockouts also display impaired spatial learning in the Morris water maze and are severely impaired in contextual fear memory, which correspond to deficits in synaptic transmission. Remarkably, the hyperactivity of the Cdk5 conditional knockouts can be ameliorated by the administration of lithium chloride, an inhibitor of GSK3ß signaling. Collectively, our data reveal that Cdk5 ablation from forebrain excitatory neurons results in deleterious effects on emotional and cognitive behavior and highlight a key role for Cdk5 in regulating the GSK3ß signaling pathway.


Assuntos
Cognição , Quinase 5 Dependente de Ciclina/metabolismo , Hipercinese/metabolismo , Prosencéfalo/metabolismo , Células Piramidais/metabolismo , Animais , Quinase 5 Dependente de Ciclina/genética , Técnicas de Inativação de Genes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
11.
Neuron ; 56(5): 823-37, 2007 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-18054859

RESUMO

Synaptogenesis is a highly regulated process that underlies formation of neural circuitry. Considerable work has demonstrated the capability of some adhesion molecules, such as SynCAM and Neurexins/Neuroligins, to induce synapse formation in vitro. Furthermore, Cdk5 gain of function results in an increased number of synapses in vivo. To gain a better understanding of how Cdk5 might promote synaptogenesis, we investigated potential crosstalk between Cdk5 and the cascade of events mediated by synapse-inducing proteins. One protein recruited to developing terminals by SynCAM and Neurexins/Neuroligins is the MAGUK family member CASK. We found that Cdk5 phosphorylates and regulates CASK distribution to membranes. In the absence of Cdk5-dependent phosphorylation, CASK is not recruited to developing synapses and thus fails to interact with essential presynaptic components. Functional consequences include alterations in calcium influx. Mechanistically, Cdk5 regulates the interaction between CASK and liprin-alpha. These results provide a molecular explanation of how Cdk5 can promote synaptogenesis.


Assuntos
Quinase 5 Dependente de Ciclina/fisiologia , Guanilato Quinases/metabolismo , Frações Subcelulares/metabolismo , Sinapses/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Transtorno Autístico/genética , Canais de Cálcio/fisiologia , Molécula 1 de Adesão Celular , Moléculas de Adesão Celular , Imunoglobulinas/biossíntese , Imunoglobulinas/genética , Ativação do Canal Iônico/fisiologia , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Camundongos , Fosforilação , Terminações Pré-Sinápticas/fisiologia , Proteínas/genética , Receptor Cross-Talk/fisiologia
12.
J Immunol ; 181(9): 6092-100, 2008 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-18941198

RESUMO

Patients and rodents with Goodpasture's syndrome (GPS) develop severe autoimmune crescentic glomerulonephritis, kidney failure, and lung hemorrhage due to binding of pathogenic autoantibodies to the NC1 domain of the alpha3 chain of type IV collagen. Target epitopes are cryptic, normally hidden from circulating Abs by protein-protein interactions and the highly tissue-restricted expression of the alpha3(IV) collagen chain. Based on this limited Ag exposure, it has been suggested that target epitopes are not available as B cell tolerogens. To determine how pathogenic anti-GPS autoantibody responses are regulated, we generated an Ig transgenic (Tg) mouse model that expresses an Ig that binds alpha3(IV)NC1 collagen epitopes recognized by serum IgG of patients with GPS. Phenotypic analysis reveals B cell depletion and L chain editing in Tg mice. To determine the default tolerance phenotype in the absence of receptor editing and endogenous lymphocyte populations, we crossed Tg mice two generations with mice deficient in Rag. Resulting Tg Rag-deficient mice have central B cell deletion. Thus, development of Tg anti-alpha3(IV)NC1 collagen B cells is halted in the bone marrow, at which point the cells are deleted unless rescued by a Rag enzyme-dependent process, such as editing. The central tolerance phenotype implies that tolerizing self-Ag is expressed in bone marrow.


Assuntos
Doença Antimembrana Basal Glomerular/imunologia , Autoantígenos/imunologia , Autoantígenos/metabolismo , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Colágeno Tipo IV/imunologia , Colágeno Tipo IV/metabolismo , Tolerância Imunológica , Animais , Doença Antimembrana Basal Glomerular/genética , Anticorpos Monoclonais/metabolismo , Autoanticorpos/biossíntese , Autoanticorpos/fisiologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Proteínas de Homeodomínio/genética , Humanos , Tolerância Imunológica/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
13.
Cell Rep ; 26(5): 1112-1127.e9, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30699343

RESUMO

The molecular basis of the earliest neuronal changes that lead to Alzheimer's disease (AD) is unclear. Here, we analyze neural cells derived from sporadic AD (SAD), APOE4 gene-edited and control induced pluripotent stem cells (iPSCs). We observe major differences in iPSC-derived neural progenitor (NP) cells and neurons in gene networks related to neuronal differentiation, neurogenesis, and synaptic transmission. The iPSC-derived neural cells from SAD patients exhibit accelerated neural differentiation and reduced progenitor cell renewal. Moreover, a similar phenotype appears in NP cells and cerebral organoids derived from APOE4 iPSCs. Impaired function of the transcriptional repressor REST is strongly implicated in the altered transcriptome and differentiation state. SAD and APOE4 expression result in reduced REST nuclear translocation and chromatin binding, and disruption of the nuclear lamina. Thus, dysregulation of neural gene networks may set in motion the pathologic cascade that leads to AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Redes Reguladoras de Genes , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios/metabolismo , Proteínas Repressoras/metabolismo , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/metabolismo , Diferenciação Celular/genética , Reprogramação Celular/genética , Fibroblastos/patologia , Regulação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Células-Tronco Neurais/metabolismo , Neurogênese/genética , Lâmina Nuclear/metabolismo
14.
Cell Death Differ ; 25(4): 648-662, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29459769

RESUMO

Although amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, was first described in 1874, a flurry of genetic discoveries in the last 10 years has markedly increased our understanding of this disease. These findings have not only enhanced our knowledge of mechanisms leading to ALS, but also have revealed that ALS shares many genetic causes with another neurodegenerative disease, frontotemporal lobar dementia (FTLD). In this review, we survey how recent genetic studies have bridged our mechanistic understanding of these two related diseases and how the genetics behind ALS and FTLD point to complex disorders, implicating non-neuronal cell types in disease pathophysiology. The involvement of non-neuronal cell types is consistent with a non-cell autonomous component in these diseases. This is further supported by studies that identified a critical role of immune-associated genes within ALS/FTLD and other neurodegenerative disorders. The molecular functions of these genes support an emerging concept that various non-autonomous functions are involved in neurodegeneration. Further insights into such a mechanism(s) will ultimately lead to a better understanding of potential routes of therapeutic intervention. Facts ALS and FTLD are severe neurodegenerative disorders on the same disease spectrum. Multiple cellular processes including dysregulation of RNA homeostasis, imbalance of proteostasis, contribute to ALS/FTLD pathogenesis. Aberrant function in non-neuronal cell types, including microglia, contributes to ALS/FTLD. Strong neuroimmune and neuroinflammatory components are associated with ALS/FTLD patients. Open Questions Why can patients with similar mutations have different disease manifestations, i.e., why do C9ORF72 mutations lead to motor neuron loss in some patients while others exhibit loss of neurons in the frontotemporal lobe? Do ALS causal mutations result in microglial dysfunction and contribute to ALS/FTLD pathology? How do microglia normally act to mitigate neurodegeneration in ALS/FTLD? To what extent do cellular signaling pathways mediate non-cell autonomous communications between distinct central nervous system (CNS) cell types during disease? Is it possible to therapeutically target specific cell types in the CNS?


Assuntos
Esclerose Lateral Amiotrófica , Proteína C9orf72 , Demência Frontotemporal , Neurônios Motores , Mutação , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Humanos , Neurônios Motores/metabolismo , Neurônios Motores/patologia
15.
Nat Neurosci ; 16(10): 1383-91, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24036913

RESUMO

Defects in DNA repair have been extensively linked to neurodegenerative diseases, but the exact mechanisms remain poorly understood. We found that FUS, an RNA/DNA-binding protein that has been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, is important for the DNA damage response (DDR). The function of FUS in DDR involved a direct interaction with histone deacetylase 1 (HDAC1), and the recruitment of FUS to double-stranded break sites was important for proper DDR signaling. Notably, FUS proteins carrying familial ALS mutations were defective in DDR and DNA repair and showed a diminished interaction with HDAC1. Moreover, we observed increased DNA damage in human ALS patients harboring FUS mutations. Our findings suggest that an impaired DDR and DNA repair may contribute to the pathogenesis of neurodegenerative diseases linked to FUS mutations.


Assuntos
Dano ao DNA/fisiologia , Histona Desacetilase 1/metabolismo , Neurônios/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Células Cultivadas , Células HEK293 , Histona Desacetilase 1/genética , Humanos , Camundongos , Neurônios/patologia , Ligação Proteica/fisiologia , Proteína FUS de Ligação a RNA/genética
17.
Neuron ; 75(4): 675-87, 2012 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-22920258

RESUMO

N-type voltage-gated calcium channels localize to presynaptic nerve terminals and mediate key events including synaptogenesis and neurotransmission. While several kinases have been implicated in the modulation of calcium channels, their impact on presynaptic functions remains unclear. Here we report that the N-type calcium channel is a substrate for cyclin-dependent kinase 5 (Cdk5). The pore-forming α(1) subunit of the N-type calcium channel is phosphorylated in the C-terminal domain, and phosphorylation results in enhanced calcium influx due to increased channel open probability. Phosphorylation of the N-type calcium channel by Cdk5 facilitates neurotransmitter release and alters presynaptic plasticity by increasing the number of docked vesicles at the synaptic cleft. These effects are mediated by an altered interaction between N-type calcium channels and RIM1, which tethers presynaptic calcium channels to the active zone. Collectively, our results highlight a molecular mechanism by which N-type calcium channels are regulated by Cdk5 to affect presynaptic function.


Assuntos
Canais de Cálcio Tipo N/fisiologia , Quinase 5 Dependente de Ciclina/metabolismo , Ativação do Canal Iônico/fisiologia , Neurônios/citologia , Fosfotransferases/metabolismo , Terminações Pré-Sinápticas/fisiologia , Amiodarona , Análise de Variância , Animais , Biofísica , Biotinilação , Canais de Cálcio Tipo N/genética , Células Cultivadas , Córtex Cerebral/citologia , Quinase 5 Dependente de Ciclina/genética , Estimulação Elétrica , Embrião de Mamíferos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Hipocampo/citologia , Humanos , Imunoprecipitação , Técnicas In Vitro , Ativação do Canal Iônico/efeitos dos fármacos , Ativação do Canal Iônico/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Modelos Moleculares , Mutação/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Neurônios/ultraestrutura , Técnicas de Patch-Clamp , Fosforilação , Fosfotransferases/genética , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/ultraestrutura , Radioimunoensaio , Análise de Sequência de Proteína
18.
Cell Stem Cell ; 9(5): 413-9, 2011 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-22019014

RESUMO

Recent advances in somatic cell reprogramming have highlighted the plasticity of the somatic epigenome, particularly through demonstrations of direct lineage reprogramming of one somatic cell type to another by defined factors. However, it is not clear to what extent this type of reprogramming is able to generate fully functional differentiated cells. In addition, the activity of the reprogrammed cells in cell transplantation assays, such as those envisaged for cell-based therapy of Parkinson's disease (PD), remains to be determined. Here we show that ectopic expression of defined transcription factors in mouse tail tip fibroblasts is sufficient to induce Pitx3+ neurons that closely resemble midbrain dopaminergic (DA) neurons. In addition, transplantation of these induced DA (iDA) neurons alleviates symptoms in a mouse model of PD. Thus, iDA neurons generated from abundant somatic fibroblasts by direct lineage reprogramming hold promise for modeling neurodegenerative disease and for cell-based therapies of PD.


Assuntos
Diferenciação Celular , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/metabolismo , Fibroblastos/citologia , Animais , Neurônios Dopaminérgicos/transplante , Perfilação da Expressão Gênica , Camundongos , Doença de Parkinson/terapia , Fatores de Transcrição/metabolismo
19.
PLoS One ; 6(9): e25735, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21984943

RESUMO

Memory formation is modulated by pre- and post-synaptic signaling events in neurons. The neuronal protein kinase Cyclin-Dependent Kinase 5 (Cdk5) phosphorylates a variety of synaptic substrates and is implicated in memory formation. It has also been shown to play a role in homeostatic regulation of synaptic plasticity in cultured neurons. Surprisingly, we found that Cdk5 loss of function in hippocampal circuits results in severe impairments in memory formation and retrieval. Moreover, Cdk5 loss of function in the hippocampus disrupts cAMP signaling due to an aberrant increase in phosphodiesterase (PDE) proteins. Dysregulation of cAMP is associated with defective CREB phosphorylation and disrupted composition of synaptic proteins in Cdk5-deficient mice. Rolipram, a PDE4 inhibitor that prevents cAMP depletion, restores synaptic plasticity and memory formation in Cdk5-deficient mice. Collectively, our results demonstrate a critical role for Cdk5 in the regulation of cAMP-mediated hippocampal functions essential for synaptic plasticity and memory formation.


Assuntos
AMP Cíclico/metabolismo , Quinase 5 Dependente de Ciclina/metabolismo , Hipocampo/metabolismo , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Transdução de Sinais/fisiologia , Animais , Southern Blotting , Quinase 5 Dependente de Ciclina/genética , Eletrofisiologia , Immunoblotting , Imuno-Histoquímica , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Plasticidade Neuronal/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética
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