Rett syndrome and environmental enrichment as a potential therapy for attenuating the pathology

Rett syndrome (RTT) is a neurological disorder affecting the development of the central nervous system and one of the leading causes of mental retardation among young women. RTT patients exhibit microcephaly, decreased neuronal size, shorter cortical dendrite, and a reduced dendritic spine density; evidence strongly suggesting that a synaptic disorder underlies the neurological RTT-associated phenotype. MECP2 is a transcription factor with multiple roles on gene expression, and mutations in its gene coding sequence have been identified as the major cause of RTT. The generation of transgenic mouse models lacking the expression of Mecp2 has allowed getting insight into the physiopathological events associated with the loss of a fully functional Mecp2 allele in RTT patients and it has been demonstrated that is possible to partially rescue, or reverse, the phenotype associated with RTT which opens a window to explore therapeutic approaches plausible to be utilized in RTT patients. Considering that RTT patients exhibit reduced neuronal plasticity and synaptic disorder, this mini-review is focused on studies demonstrating the positive effect of an enriched environment on the RTT-like phenotype exhibited by mouse models of the disease.Sociedad Argentina de Fisiologí

Epigenetic Modification Mechanisms Involved in Inflammation and Fibrosis in Renal Pathology

The growing incidence of obesity, hypertension, and diabetes, coupled with the aging of the population, is increasing the prevalence of renal diseases in our society. Chronic kidney disease (CKD) is characterized by persistent inflammation, fibrosis, and loss of renal function leading to end-stage renal disease. Nowadays, CKD treatment has limited effectiveness underscoring the importance of the development of innovative therapeutic options. Recent studies have identified how epigenetic modifications participate in the susceptibility to CKD and have explained how the environment interacts with the renal cell epigenome to contribute to renal damage. Epigenetic mechanisms regulate critical processes involved in gene regulation and downstream cellular responses. The most relevant epigenetic modifications that play a critical role in renal damage include DNA methylation, histone modifications, and changes in miRNA levels. Importantly, these epigenetic modifications are reversible and, therefore, a source of potential therapeutic targets. Here, we will explain how epigenetic mechanisms may regulate essential processes involved in renal pathology and highlight some possible epigenetic therapeutic strategies for CKD treatment.This work was supported by Instituto de Salud Carlos III and Fondos FEDER European Union (PI14/00041, PI15/00960, PI16/01354, PI17/00119, and PI17/01244), Red de Investigación Renal (REDinREN; RD16/0009), Comunidad de Madrid (B2017/BMD-3751 NOVELREN-CM), Fondecyt 1181574 (BK), Sociedad Española de Nefrología, and the “Juan de la Cierva Formacion” training program of the Ministerio de Economia, Industria y Competitividad which supported the salary of S.R-M (FJCI-2016-29050). V. Marchant has a CONICYT Scholarship for his graduate studies at the PhD program in Medical Science, Universidad Austral de Chile. The Centro de Estudios Científicos is funded by the Chilean Government through the Centers of Excellence Basal Financing Program of CONICYT

The Proteasomal Deubiquitinating Enzyme PSMD14 Regulates Macroautophagy by Controlling Golgi-to-ER Retrograde Transport

Ubiquitination regulates several biological processes, however the role of specific members of the ubiquitinome on intracellular membrane trafficking is not yet fully understood. Here, we search for ubiquitin-related genes implicated in protein membrane trafficking performing a High-Content siRNA Screening including 1187 genes of the human “ubiquitinome” using amyloid precursor protein (APP) as a reporter. We identified the deubiquitinating enzyme PSMD14, a subunit of the 19S regulatory particle of the proteasome, specific for K63-Ub chains in cells, as a novel regulator of Golgi-to-endoplasmic reticulum (ER) retrograde transport. Silencing or pharmacological inhibition of PSMD14 with Capzimin (CZM) caused a robust increase in APP levels at the Golgi apparatus and the swelling of this organelle. We showed that this phenotype is the result of rapid inhibition of Golgi-to-ER retrograde transport, a pathway implicated in the early steps of the autophagosomal formation. Indeed, we observed that inhibition of PSMD14 with CZM acts as a potent blocker of macroautophagy by a mechanism related to the retention of Atg9A and Rab1A at the Golgi apparatus. As pharmacological inhibition of the proteolytic core of the 20S proteasome did not recapitulate these effects, we concluded that PSMD14, and the K63-Ub chains, act as a crucial regulatory factor for macroautophagy by controlling Golgi-to-ER retrograde transport

Unconventional Transcriptional Response to Environmental Enrichment in a Mouse Model of Rett Syndrome

Background: Rett syndrome (RTT) is an X-linked postnatal neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2) and one of the leading causes of mental retardation in females. RTT is characterized by psychomotor retardation, purposeless hand movements, autistic-like behavior and abnormal gait. We studied the effects of environmental enrichment (EE) on the phenotypic manifestations of a RTT mouse model that lacks MeCP2 (Mecp2 2/y). Principal Findings: We found that EE delayed and attenuated some neurological alterations presented by Mecp2 2/y mice and prevented the development of motor discoordination and anxiety-related abnormalities. To define the molecular correlate of this beneficial effect of EE, we analyzed the expression of several synaptic marker genes whose expression is increased by EE in several mouse models. Conclusions/Significance: We found that EE induced downregulation of several synaptic markers, suggesting that th

Spatial Learning Is Associated with Antagonist Outcomes for DNA Methylation and DNA Hydroxymethylation in the Transcriptional Regulation of the Ryanodine Receptor 3

Increasing attention has been drawn to the role that intracellular calcium stores play in neuronal function. Ryr3 is an intracellular calcium channel that contributes to hippocampal long-term potentiation, dendritic spine function, and higher cognitive processes. Interestingly, stimuli that increase neuronal activity upregulate the transcriptional activity of Ryr3 and augment DNA methylation in its proximal promoter. However, if these observations are valid for complex behavioral tasks such as learning and memory remains being evaluated. Relative expression analysis revealed that spatial learning increased the hippocampal levels of Ryr3, whereas mice trained using a visible platform that resulted in no spatial association showed reduced expression. Interestingly, we also observed that specific DNA modifications accompanied these opposite transcriptional changes. Increased DNA methylation was observed in hippocampal samples from spatially trained mice, and increased DNA hydroxymethylation was found in samples from mice trained using a visible platform. Both DNA modifications were not altered in control regions, suggesting that these changes are not generalized, but rather specific modifications associated with this calcium channel’s transcriptional regulation. Our two experimental groups underwent the same physical task differing only in the spatial learning component, highlighting the tight relationship between DNA modifications and transcriptional activity in a relevant context such as behavioral training. Our results complement previous observations and suggest that DNA modifications are a reliable signal for the transcriptional activity of Ryr3 and can be useful to understand how conditions such as aging and neuropathological diseases determine altered Ryr3 expression

Mecp2 mediates experience-dependent transcriptional upregulation of ryanodine receptor type-3

Mecp2 is a DNA methylation reader that plays a critical role in experience-dependent plasticity. Increasing evidence supports a role for epigenetic modifications in activity-induced gene expression. Hence, candidate genes related to such phenomena are of great interest. Ryanodine receptors are intracellular calcium channels that contribute to hippocampal synaptic plasticity, dendritic spine remodeling, and participate in learning and memory processes. Here we exposed mice to the enriched environment (EE) paradigm, which through increased stimulation induces experience dependent-plasticity, to explore a role for methyl-cytosines, and Mecp2 in directing Ryanodine receptor 3 (Ryr3) transcriptional activity. EE induced a hippocampal-specific increase in the methylation of discrete cytosines located at a Ryr3 isoform promoter; chromatin immunoprecipitation experiments revealed that EE increased Mecp2 binding to this Ryr3 isoform promoter. Interestingly, the experimental paradigm induced robust Ryr3 upregulation, accompanied by miR132-dependent suppression of p250GAP, a pathway driving synaptogenesis. In contrast to WT mice, Mecp2-null mice showed diminished levels of Ryr3 and displayed impaired EE-induced Ryr3 upregulation, compromising miR132 dependent suppression of p250GAP and experience-dependent structural plasticity. Based on these results, we propose that Mecp2 acts as a transcriptional activator of Ryr3, contributing to experience- dependent plasticity.Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT), 1140162, 1140545 / Biomedical Neuroscience Institute, BNI P-09-015F Chilean Government through the Centers of Excellence Basal Financing Program of CONICY

DNA methylation changes in genes coding for leptin and insulin receptors during metabolic-altered pregnancies

The overwhelming rates of obesity worldwide are a major concern due to the elevated medical costs associated and the poor quality of life of obese patients. In the recent years, it has become evident that the intrauterine milieu can have a long-term impact on the foetus health. The placenta is a highly dynamic organ; whose primary function is to carry nutrients from the mother to the foetus and to remove waste products from the foetus. Any alteration in maternal circulating metabolites elicits a response in order to ensure the developing foetus an adequate growth environment. This response can be translated into epigenetic modifications in coding genes for metabolic-related receptors located in the placenta and foetal tissues. The most studied receptors involved in the metabolic sensing are the leptin and the insulin receptors. A maternal metabolic disease-like state can alter the expression of these receptors in different organs, including placenta. There is evidence that these alterations not only affect the expression level of these receptors, but there are also differences in epigenetic marks in regulatory elements of these genes that may become permanent despite the mother's treatment. This review provides evidence about possible mechanisms involved in the foetal programming of metabolic diseases originated from the pre-natal environment that could contributive to increasing levels of obesity in the world

Environmental Enrichment restores a normal behavior in the plus maze test.

<p>A, In the elevated plus maze, significant increases in the percentage of time spent in open arms were seen in <i>Mecp2^−/y</i>-SC (129 genetic background) compared with <i>Mecp2^+/y</i>-SC mice. This phenotype is reversed in the <i>Mecp2^−/y</i>-EE mice. B, In a B6129 F1 genetic background, <i>Mecp2^−/y</i>-EE mice showed a behavior indistinguishable from the <i>Mecp2^+/y</i>-SC mice. Mean ± SEM are presented. Two way ANOVA (genotype×condition) demonstrated differences in the mean values among the different levels of Genotype (F = 10.705; p = 0.003) and condition (F = 7.516; p = 0.011). Post hoc Student's t test detected statistical differences between groups, *: p<0.05.</p

Defective body-weight regulation, motor control and abnormal social interactions in Mecp2 hypomorphic mice

MeCP2 is an abundant protein that binds to methylated cytosine residues in DNA and regulates transcription. Mutations in MECP2 cause Rett syndrome, a severe neurological disorder that affects approximately 1:10 000 females. Mice lacking MeCP2 have been generated and constitute important models of Rett syndrome. However, it is yet unclear whether certain physiological events are sensitive to a decrease, rather than a complete lack of MeCP2. Here we report that a Mecp2 floxed allele (Mecp2 lox ) that was generated to allow conditional mutagenesis behaves as a hypomorph and the corresponding mutant mice exhibit phenotypical alterations including body weight gain, motor abnormalities and altered social behavior. Our data reinforce the view that the central nervous system is extremely sensitive to MeCP2 expression levels and suggest that the 3′-UTR of Mecp2 might contain important elements that contribute to the regulation of its stability or processing