Editorial: Epigenetic Mechanisms Regulating Neural Plasticity.

While larger parts of the genome have been deciphered and sequenced during the last decade, it is now possible to identify practically all the genes that a cell or tissue transcribes and translates at a given moment in time (Wheeler et al., 2008). Thus, the challenge we are now facing is to understand the epigenetic regulation of all this information, it will be the next great task in the near future. The central nervous system (CNS), and especially the brain, has evolved to make humans the way they are, and it is strongly influenced and affected by epigenetic factors (Stroud et al., 2017)..

Pleiotrophin as a central nervous system neuromodulator, evidences from the hippocampus

Pleiotrophin (PTN) is a secreted growth factor, and also a cytokine, associated with the extracellular matrix, which has recently starting to attract attention as a significant neuromodulator with multiple neuronal functions during development. PTN is expressed in several tissues, where its signals are generally related with cell proliferation, growth, and differentiation by acting through different receptors. In Central Nervous System (CNS), PTN exerts post-developmental neurotrophic and -protective effects, and additionally has been involved in neurodegenerative diseases and neural disorders. Studies in Drosophila shed light on some aspects of the different levels of regulatory control of PTN invertebrate homologs. Specifically in hippocampus, recent evidence from PTN Knock-out (KO) mice involves PTN functioning in learning and memory. In this paper, we summarize, discuss, and contrast the most recent advances and results that lead to proposing a PTN as a neuromodulatory molecule in the CNS, particularly in hippocampus

The Role of the miR-17-92 Cluster in Autophagy and Atherosclerosis Supports Its Link to Lysosomal Storage Diseases

Establishing the role of non-coding RNA (ncRNA), especially microRNAs (miRNAs), in the regulation of cell function constitutes a current research challenge. Two to six miRNAs can act in clusters; particularly, the miR-17-92 family, composed of miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92a is well-characterized. This cluster functions during embryonic development in cell differentiation, growth, development, and morphogenesis and is an established oncogenic cluster. However, its role in the regulation of cellular metabolism, mainly in lipid metabolism and autophagy, has received less attention. Here, we argue that the miR-17-92 cluster is highly relevant for these two processes, and thus, could be involved in the study of pathologies derived from lysosomal deficiencies. Lysosomes are related to both processes, as they control cholesterol flux and regulate autophagy. Accordingly, we compiled, analyzed, and discussed current evidence that highlights the cluster's fundamental role in regulating cellular energetic metabolism (mainly lipid and cholesterol flux) and atherosclerosis, as well as its critical participation in autophagy regulation. Because these processes are closely related to lysosomes, we also provide experimental data from the literature to support our proposal that the miR-17-92 cluster could be involved in the pathogenesis and effects of lysosomal storage diseases (LSD)

Environmental Enrichment Modified Epigenetic Mechanisms in SAMP8 Mouse Hippocampus by Reducing Oxidative Stress and Inflammaging and Achieving Neuroprotection

With the increase in life expectancy, aging and age-related cognitive impairments arebecoming one of the most important issues for human health. At the same time, ithas been shown that epigenetic mechanisms are emerging as universally importantfactors in life expectancy. The Senescence Accelerated Mouse P8 (SAMP8) strainexhibits age-related deterioration evidenced in learning and memory abilities and is auseful model of neurodegenerative disease. In SAMP8, Environmental Enrichment (EE)increased DNA-methylation levels (5-mC) and reduced hydroxymethylation levels (5-hmC), as well as increased histone H3 and H4 acetylation levels. Likewise, we foundchanges in the hippocampal gene expression of some chromatin-modifying enzymegenes, such asDnmt3b,Hdac1,Hdac2,Sirt2, andSirt6.Subsequently, we assessedthe effects of EE on neuroprotection-related transcription factors, such as the Nuclearregulatory factor 2 (Nrf2)-Antioxidant Response Element pathway and Nuclear Factorkappa Beta (NF-κB), which play critical roles in inflammation. We found that EE producesan increased expression of antioxidant genes, such asHmox1,Aox1, andCox2, andreduced the expression of inflammatory genes such asIL-6andCxcl10, all of this withinthe epigenetic context modified by EE. In conclusion, EE prevents epigenetic changesthat promote or drive oxidative stress and inflammagin

Cognitive Decline and BPSD Are Concomitant with Autophagic and Synaptic Deficits Associated with G9a Alterations in Aged SAMP8 Mice

Behavioural and psychological symptoms of dementia (BPSD) are presented in 95% of Alzheimer's Disease (AD) patients and are also associated with neurotrophin deficits. The molecular mechanisms leading to age-related diseases are still unclear; however, emerging evidence has suggested that epigenetic modulation is a key pathophysiological basis of ageing and neurodegeneration. In particular, it has been suggested that G9a methyltransferase and its repressive histone mark (H3K9me2) are important in shaping learning and memory by modulating autophagic activity and synaptic plasticity. This work deepens our understanding of the epigenetic mechanisms underlying the loss of cognitive function and BPSD in AD. For this purpose, several tasks were performed to evaluate the parameters of sociability (three-chamber test), aggressiveness (resident intruder), anxiety (elevated plus maze and open field) and memory (novel object recognition test) in mice, followed by the evaluation of epigenetic, autophagy and synaptic plasticity markers at the molecular level. The behavioural alterations presented by senescence-accelerated mice prone 8 (SAMP8) of 12 months of age compared with their senescence-accelerated mouse resistant mice (SAMR1), the healthy control strain was accompanied by age-related cognitive deficits and alterations in epigenetic markers. Increased levels of G9a are concomitant to the dysregulation of the JNK pathway in aged SAMP8, driving a failure in autophagosome formation. Furthermore, lower expression of the genes involved in the memory-consolidation process modulated by ERK was observed in the aged male SAMP8 model, suggesting the implication of G9a. In any case, two of the most important neurotrophins, namely brain-derived neurotrophic factor (Bdnf) and neurotrophin-3 (NT3), were found to be reduced, along with a decrease in the levels of dendritic branching and spine density presented by SAMP8 mice. Thus, the present study characterizes and provides information regarding the non-cognitive and cognitive states, as well as molecular alterations, in aged SAMP8, demonstrating the AD-like symptoms presented by this model. In any case, our results indicate that higher levels of G9a are associated with autophagic deficits and alterations in synaptic plasticity, which could further explain the BPSD and cognitive decline exhibited by the model