Conserved reduction of m6A RNA modifications during aging and neurodegeneration is linked to changes in synaptic transcripts.

N6-methyladenosine (m6A) regulates mRNA metabolism. While it has been implicated in the development of the mammalian brain and in cognition, the role of m6A in synaptic plasticity, especially during cognitive decline, is not fully understood. In this study, we employed methylated RNA immunoprecipitation sequencing to obtain the m6A epitranscriptome of the hippocampal subregions CA1, CA3, and the dentate gyrus and the anterior cingulate cortex (ACC) in young and aged mice. We observed a decrease in m6A levels in aged animals. Comparative analysis of cingulate cortex (CC) brain tissue from cognitively intact human subjects and Alzheimer's disease (AD) patients showed decreased m6A RNA methylation in AD patients. m6A changes common to brains of aged mice and AD patients were found in transcripts linked to synaptic function including calcium/calmodulin-dependent protein kinase 2 (CAMKII) and AMPA-selective glutamate receptor 1 (Glua1). We used proximity ligation assays to show that reduced m6A levels result in decreased synaptic protein synthesis as exemplified by CAMKII and GLUA1. Moreover, reduced m6A levels impaired synaptic function. Our results suggest that m6A RNA methylation controls synaptic protein synthesis and may play a role in cognitive decline associated with aging and AD.

Auditorías: su impacto en los costos de evaluación del proceso innovación en la universidad médica de Matanzas

Introducción: Medir el desempeño de las actividades científicas y de innovación a través de las auditorías, obedece a la escasa disponibilidad de recursos y a la consecuente necesidad de concursar por ellos. Objetivo: Evaluar el impacto de las auditorias de calidad y académicas sobre los costos de evaluación en el proceso Gestión de la Innovación en la Universidad de Ciencias Médicas de Matanzas. Materiales y métodos: Se realizó una investigación científica, explicativa, que se fundamenta en el paradigma mixto, donde se aplicó el procedimiento para el cálculo de los costos de la calidad. Resultados: Se observó una disminución en los costos de prevención, de un 53 % a un 50 %. No así en los costos de evaluación, donde ascendieron de un 15 % a 31 %, por concepto de gastos incurridos en los procesos de auditorías. Conclusiones: El empleo de las auditorias académicas y de calidad como herramientas de control induce a un incremento en los costos de evaluación de la calidad, lo que favorece una mayor eficiencia en los resultados del proceso de gestión de la innovación de la Universidad de Ciencias Médicas de Matanzas.

Introduction: Measuring the performance of scientific and innovation activities through audits, is due to the limited availability of resources and the consequent need to compete for them. Objective: To assess the impact of quality and academic audits on evaluation costs in the Innovation Management process at the Matanzas University of Medical Sciences. Materials and methods: A scientific, explanatory investigation was carried out, based on the mixed paradigm, where the procedure for the calculation of quality costs was applied. Results: A decrease in prevention costs was observed, from 53% to 50%. Not so in the evaluation costs where they rose from 15% to 31% due to expenses incurred in the audit processes. Conclusions: The use of academic and quality audits as control tools induces an increase in the costs of quality evaluation, which favors greater efficiency in the results of the innovation management process of the Matanzas University of Medical Sciences.

RBM15 Modulates the Function of Chromatin Remodeling Factor BAF155 Through RNA Methylation in Developing Cortex.

Chromatin remodeling factor BAF155 is an important regulator of many biological processes. As a core and scaffold subunit of the BAF (SWI/SNF-like) complex, BAF155 is capable of regulating the stability and function of the BAF complex. The spatiotemporal expression of BAF155 during embryogenesis is essential for various aspects of organogenesis, particularly in the brain development. However, our understanding of the mechanisms that regulate the expression and function of BAF155 is limited. Here, we report that RBM15, a subunit of the m6A methyltransferase complex, interacts with BAF155 mRNA and mediates BAF155 mRNA degradation through the mRNA methylation machinery. Ablation of endogenous RBM15 expression in cultured neuronal cells and in the developing cortex augmented the expression of BAF155. Conversely, RBM15 overexpression decreased BAF155 mRNA and protein levels, and perturbed BAF155 functions in vivo, including repression of BAF155-dependent transcriptional activity and delamination of apical radial glial progenitors as a hallmark of basal radial glial progenitor genesis. Furthermore, we demonstrated that the regulation of BAF155 by RBM15 depends on the activity of the mRNA methylation complex core catalytic subunit METTL3. Altogether, our findings reveal a new regulatory avenue that elucidates how BAF complex subunit stoichiometry and functional modulation are achieved in mammalian cells.

ATP-Dependent Chromatin Remodeling During Cortical Neurogenesis.

The generation of individual neurons (neurogenesis) during cortical development occurs in discrete steps that are subtly regulated and orchestrated to ensure normal histogenesis and function of the cortex. Notably, various gene expression programs are known to critically drive many facets of neurogenesis with a high level of specificity during brain development. Typically, precise regulation of gene expression patterns ensures that key events like proliferation and differentiation of neural progenitors, specification of neuronal subtypes, as well as migration and maturation of neurons in the developing cortex occur properly. ATP-dependent chromatin remodeling complexes regulate gene expression through utilization of energy from ATP hydrolysis to reorganize chromatin structure. These chromatin remodeling complexes are characteristically multimeric, with some capable of adopting functionally distinct conformations via subunit reconstitution to perform specific roles in major aspects of cortical neurogenesis. In this review, we highlight the functions of such chromatin remodelers during cortical development. We also bring together various proposed mechanisms by which ATP-dependent chromatin remodelers function individually or in concert, to specifically modulate vital steps in cortical neurogenesis.

Chromatin Remodeling BAF155 Subunit Regulates the Genesis of Basal Progenitors in Developing Cortex.

The abundance of basal progenitors (BPs), basal radial glia progenitors (bRGs) and basal intermediate progenitors (bIPs), in primate brain has been correlated to the high degree of cortical folding. Here we examined the role of BAF155, a subunit of the chromatin remodeling BAF complex, in generation of cortical progenitor heterogeneity. The conditional deletion of BAF155 led to diminished bIP pool and increased number of bRGs, due to delamination of apical RGs. We found that BAF155 is required for normal activity of neurogenic transcription factor PAX6, thus controlling the expression of genes that are involved in bIP specification, cell-cell interaction, and establishment of adherens junction. In a PAX6-dependent manner, BAF155 regulates the expression of the CDC42 effector protein CEP4, thereby controlling progenitor delamination. Furthermore, BAF155-dependent chromatin remodeling seems to exert a specific role in the genesis of BPs through the regulation of human RG-specific genes (such as Foxn4) that possibly acquired evolutionary significance.