RESUMEN
Age-related hearing loss (ARHL) is the most frequent sensory disorder in the elderly, affecting approximately one-third of people aged more than 65 years. Despite a large number of people affected, ARHL is still an area of unmet clinical needs, and only a few ARHL susceptibility genes have been detected so far. In order to further investigate the genetics of ARHL, we analyzed a series of 46 ARHL candidate genes, selected according to previous Genome Wide Association Studies (GWAS) data, literature updates and animal models, in a large cohort of 464 Italian ARHL patients. We have filtered the variants according to a) pathogenicity prediction, b) allele frequency in public databases, c) allele frequency in an internal cohort of 113 healthy matched controls, and 81 healthy semi-supercentenarians. After data analysis, all the variants of interest have been tested by functional "in silico" or "in vitro" experiments (i.e., molecular dynamics simulations and protein translation analysis) to assess their pathogenic role, and the expression of the mutated genes have been checked in mouse or zebrafish inner ear. This multi-step approach led to the characterization of a series of ultra-rare likely pathogenic variants in DCLK1, SLC28A3, CEP104, and PCDH20 genes, contributing to describe the first association of these genes with ARHL in humans. These results provide essential insights on the understanding of the molecular bases of such a complex, heterogeneous and frequent disorder, unveiling new possible targets for the future development of innovative therapeutic and preventive approaches that could improve the quality of life of the millions of people affected worldwide.
Asunto(s)
Predisposición Genética a la Enfermedad , Células Ciliadas Auditivas/patología , Presbiacusia/genética , Anciano , Anciano de 80 o más Años , Animales , Audiometría , Cadherinas/genética , Cadherinas/metabolismo , Estudios de Casos y Controles , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Estudios de Cohortes , Quinasas Similares a Doblecortina , Femenino , Perfilación de la Expresión Génica , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Italia , Masculino , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Ratones , Persona de Mediana Edad , Modelos Animales , Mutación , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Polimorfismo de Nucleótido Simple , Presbiacusia/diagnóstico , Presbiacusia/patología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Protocadherinas , Índice de Severidad de la Enfermedad , Secuenciación Completa del Genoma , Pez CebraRESUMEN
Along with neuronal mechanisms devoted to memory consolidation -including long term potentiation of synaptic strength as prominent electrophysiological correlate, and inherent dendritic spines stabilization as structural counterpart- negative control of memory formation and synaptic plasticity has been described at the molecular and behavioral level. Within this work, we report a role for the epigenetic corepressor Lysine Specific Demethylase 1 (LSD1) as a negative neuroplastic factor whose stress-enhanced activity may participate in coping with adverse experiences. Constitutively increasing LSD1 activity via knocking out its dominant negative splicing isoform neuroLSD1 (neuroLSD1KO mice), we observed extensive structural, functional and behavioral signs of excitatory decay, including disrupted memory consolidation. A similar LSD1 increase, obtained with acute antisense oligonucleotide-mediated neuroLSD1 splicing knock down in primary neuronal cultures, dampens spontaneous glutamatergic transmission, reducing mEPSCs. Remarkably, LSD1 physiological increase occurs in response to psychosocial stress-induced glutamatergic signaling. Since this mechanism entails neuroLSD1 splicing downregulation, we conclude that LSD1/neuroLSD1 ratio modulation in the hippocampus is instrumental to a negative homeostatic feedback, restraining glutamatergic neuroplasticity in response to glutamate. The active process of forgetting provides memories with salience. With our work, we propose that softening memory traces of adversities could further represent a stress-coping process in which LSD1/neuroLSD1 ratio modulation may help preserving healthy emotional references.
RESUMEN
Ampa receptors mediate the majority of excitatory synaptic transmission in the brain. Thus, the mechanisms that control the developmental and activity-dependent changes in the functional synaptic expression of AMPA receptors are of fundamental importance. Here we focus on the role of GluR2 subunit in synaptic function and plasticity.
Asunto(s)
Ácido Glutámico/metabolismo , Receptores AMPA/metabolismo , Sinapsis/metabolismo , Membranas Sinápticas/metabolismo , Transmisión Sináptica/fisiología , Animales , Canales de Calcio/química , Canales de Calcio/metabolismo , Humanos , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Plasticidad Neuronal/fisiología , Estructura Terciaria de Proteína/fisiología , Transporte de Proteínas/fisiología , Receptores AMPA/química , Sinapsis/ultraestructura , Membranas Sinápticas/ultraestructuraRESUMEN
La cría de salmónidos en jaulas flotantes en el embalse Alicurá es una actividad productiva que debe ser controlada a fin de minimizar sus consecuencias contaminantes y obtener una producción sostenida en el tiempo
Asunto(s)
Argentina , Contaminación de Lagos y Embalses , AcuiculturaRESUMEN
La cría de salmónidos en jaulas flotantes en el embalse Alicurá es una actividad productiva que debe ser controlada a fin de minimizar sus consecuencias contaminantes y obtener una producción sostenida en el tiempo