RESUMEN
Defects in DNA repair have been linked to cognitive decline with age and neurodegenerative disease, yet the mechanisms that protect neurons from genotoxic stress remain largely obscure. We sought to characterize the roles of the NAD(+)-dependent deacetylase SIRT1 in the neuronal response to DNA double-strand breaks (DSBs). We found that SIRT1 was rapidly recruited to DSBs in postmitotic neurons, where it showed a synergistic relationship with ataxia telangiectasia mutated (ATM). SIRT1 recruitment to breaks was ATM dependent; however, SIRT1 also stimulated ATM autophosphorylation and activity and stabilized ATM at DSB sites. After DSB induction, SIRT1 also bound the neuroprotective class I histone deacetylase HDAC1. We found that SIRT1 deacetylated HDAC1 and stimulated its enzymatic activity, which was necessary for DSB repair through the nonhomologous end-joining pathway. HDAC1 mutations that mimic a constitutively acetylated state rendered neurons more susceptible to DNA damage, whereas pharmacological SIRT1 activators that promoted HDAC1 deacetylation also reduced DNA damage in two mouse models of neurodegeneration. We propose that SIRT1 is an apical transducer of the DSB response and that SIRT1 activation offers an important therapeutic avenue in neurodegeneration.
Asunto(s)
Proteínas de Ciclo Celular/fisiología , Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades/fisiología , Proteínas de Unión al ADN/fisiología , Inestabilidad Genómica , Histona Desacetilasa 1/fisiología , Neuronas/metabolismo , Proteínas Serina-Treonina Quinasas/fisiología , Sirtuina 1/fisiología , Proteínas Supresoras de Tumor/fisiología , Acetilación , Secuencia de Aminoácidos , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Línea Celular , Corteza Cerebral/citología , Ensayo Cometa , Activación Enzimática/efectos de los fármacos , Etopósido/farmacología , Vectores Genéticos , Células HEK293 , Hipocampo/citología , Histona Desacetilasa 1/genética , Histona Desacetilasa 1/inmunología , Humanos , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Fosforilación , Mapeo de Interacción de Proteínas , Procesamiento Proteico-Postraduccional , Interferencia de ARN , ARN Interferente Pequeño/farmacología , Proteínas Recombinantes de Fusión/fisiología , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/genéticaRESUMEN
Over the past decade, it has become increasingly obvious that epigenetic mechanisms are an integral part of a multitude of brain functions that range from the development of the nervous system over basic neuronal functions to higher order cognitive processes. At the same time, a substantial body of evidence has surfaced indicating that several neurodevelopmental, neurodegenerative, and neuropsychiatric disorders are in part caused by aberrant epigenetic modifications. Because of their inherent plasticity, such pathological epigenetic modifications are readily amenable to pharmacological interventions and have thus raised justified hopes that the epigenetic machinery provides a powerful new platform for therapeutic approaches against these diseases. In this review, we give a detailed overview of the implication of epigenetic mechanisms in both physiological and pathological brain processes and summarize the state-of-the-art of "epigenetic medicine" where applicable. Despite, or because of, these new and exciting findings, it is becoming apparent that the epigenetic machinery in the brain is highly complex and intertwined, which underscores the need for more refined studies to disentangle brain-region and cell-type specific epigenetic codes in a given environmental condition. Clearly, the brain contains an epigenetic "hotspot" with a unique potential to not only better understand its most complex functions, but also to treat its most vicious diseases.
Asunto(s)
Química Encefálica/genética , Encefalopatías/genética , Epigénesis Genética/fisiología , Epigenómica , Expresión Génica/fisiología , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Genes del Desarrollo/genética , Genes del Desarrollo/fisiología , Humanos , Trastornos Mentales/genética , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Terminología como AsuntoRESUMEN
Aberrant cell-cycle activity and DNA damage are emerging as important pathological components in various neurodegenerative conditions. However, their underlying mechanisms are poorly understood. Here, we show that deregulation of histone deacetylase 1 (HDAC1) activity by p25/Cdk5 induces aberrant cell-cycle activity and double-strand DNA breaks leading to neurotoxicity. In a transgenic model for neurodegeneration, p25/Cdk5 activity elicited cell-cycle activity and double-strand DNA breaks that preceded neuronal death. Inhibition of HDAC1 activity by p25/Cdk5 was identified as an underlying mechanism for these events, and HDAC1 gain of function provided potent protection against DNA damage and neurotoxicity in cultured neurons and an in vivo model for ischemia. Our findings outline a pathological signaling pathway illustrating the importance of maintaining HDAC1 activity in the adult neuron. This pathway constitutes a molecular link between aberrant cell-cycle activity and DNA damage and is a potential target for therapeutics against diseases and conditions involving neuronal death.
Asunto(s)
Quinasa 5 Dependiente de la Ciclina/fisiología , Histona Desacetilasas/metabolismo , Degeneración Nerviosa/enzimología , Animales , Animales Recién Nacidos , Ciclo Celular/fisiología , Células Cultivadas , Corteza Cerebral/citología , Inmunoprecipitación de Cromatina/métodos , Homólogo de la Proteína Chromobox 5 , Ensayo Cometa , Condicionamiento Psicológico/fisiología , Quinasa 5 Dependiente de la Ciclina/genética , Roturas del ADN de Doble Cadena , Daño del ADN/genética , Miedo/fisiología , Expresión Génica/genética , Perfilación de la Expresión Génica/métodos , Proteínas Fluorescentes Verdes/biosíntesis , Proteínas Fluorescentes Verdes/genética , Histona Desacetilasa 1 , Humanos , Isquemia/patología , Antígeno Ki-67/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Degeneración Nerviosa/genética , Tejido Nervioso/metabolismo , Neuronas/fisiología , Antígeno Nuclear de Célula en Proliferación/metabolismo , Prosencéfalo/metabolismo , Ratas , TransfecciónRESUMEN
A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Esclerosis Amiotrófica Lateral/metabolismo , Degeneración Nerviosa/metabolismo , Sirtuinas/metabolismo , Acetilación/efectos de los fármacos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Animales , Células Cultivadas , Quinasa 5 Dependiente de la Ciclina/metabolismo , Modelos Animales de Enfermedad , Activación Enzimática , Regulación de la Expresión Génica , Humanos , Ratones , Ratones Transgénicos , Mutación/genética , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Ratas , Resveratrol , Sirtuina 1 , Sirtuinas/genética , Estilbenos/farmacología , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1 , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Aberrant processing of the amyloid precursor protein (APP) and the subsequent accumulation of amyloid beta (Abeta) peptide has been widely established as a central event in Alzheimer's disease (AD) pathogenesis. The sequential cleavage steps required for the generation of Abeta are well outlined; however, there is a relative dearth of knowledge pertaining to signaling pathways and molecular mechanisms that can modulate this process. Here, we demonstrate a novel role for p25/cyclin-dependent kinase 5 (Cdk5) in regulating APP processing, Abeta peptide generation, and intraneuronal Abeta accumulation in inducible p25 transgenic and compound PD-APP transgenic mouse models that demonstrate deregulated Cdk5 activity and a neurodegenerative phenotype. Induction of p25 resulted in enhanced forebrain Abeta levels before any evidence of neuropathology in these mice. Intracellular Abeta accumulated in perinuclear regions and distended axons within the forebrains of these mice. Evidence for modulations in axonal transport or beta-site APP cleaving enzyme 1 protein levels and activity are presented as mechanisms that may account for the Abeta accumulation caused by p25/Cdk5 deregulation. Collectively, these findings delineate a novel pathological mechanism involving aberrant APP processing by p25/Cdk5 and have important implications in AD pathogenesis.