1,721,066 research outputs found
The 'golden age' of DNA methylation in neurodegenerative diseases
No full textDNA methylation reactions are regulated, in the first instance, by enzymes and the intermediates that constitute the 'so called' one-carbon metabolism. This is a complex biochemical pathway, also known as the homocysteine cycle, regulated by the presence of B vitamins (folate, B6, B12) and choline, among other metabolites. One of the intermediates of this metabolism is S-adenosylmethionine, which represent the methyl donor in all the DNA methyltransferase reactions in eukaryotes. The one-carbon metabolism therefore produces the substrate necessary for the transferring of a methyl group on the cytosine residues of DNA; S-adenosylmethionine also regulates the activity of the enzymes that catalyze this reaction, namely the DNA methyltransferases (DNMTs). Alterations of this metabolic cycle can therefore be responsible for aberrant DNA methylation processes possibly leading to several human diseases. As a matter of fact, increasing evidences indicate that a number of human diseases with multifactorial origin may have an epigenetic basis. This is also due to the great technical advances in the field of epigenetic research. Among the human diseases associated with epigenetic factors, aging-related and neurodegenerative diseases are probably the object of most intense research. This review will present the main evidences linking seve ral human diseases to DNA methylation, with particular focus on neurodegenerative diseases, together with a short description of the state-of-the-art of methylation assays
Nutrition-Based Modulation of Poly-ADP-Ribosylation and its possible role in Alzheimer’s disease
Full text linkAlzheimer’s Disease (AD) is the most common neurodegenerative disease and the main reason of dementia in the elderly. On the pathological point of view, it is characterized by extracellular aggregates of amyloid peptides and intracellular deposits of tau protein. These deposits affect neuron viability and functions by inducing (among other pathological pathways) oxidative stress and triggering mitochondrial dysfunction. It is now evident that free radicalinduced oxidative damage is strongly involved in the pathogenesis of AD.
Oxidative damage occurs early in disease pathogenesis and can exacerbate its progression. Post-mortem brain of individuals affected by AD, evidenced an extensive state of oxidative stress compared to healthy controls; markers of increased oxidation include, among others, DNA damage. DNA damage can induce the activity of the enzyme poly (ADP-ribose) polymerase 1 (PARP-1) that catalyze the reaction of poly (ADP-ribosylation). This post-translational modification modulates the functions of proteins involved in many physiological processes such as gene expression, maintenance of genomic stability and cell death. Therefore, inhibiting PARP-1 activity can represent a possible new strategy to reduce the impact of the oxidative stress in AD as well as in other neurodegenerative diseases. Here we discuss the role of nutrients in modulating PARP-1 activity and its perspective potential application
S-adenosylmethionine and derivatives thereof for the treatment and prevention of Alzheimer Disease
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Nicotine Restores Wt-Like Levels of Reelin and GAD67 Gene Expression in Brain of Heterozygous Reeler Mice
No full textImportant reduction of reelin, a neural development- and plasticity-associated protein, and glutamic acid decarboxylase (GAD67) are reported in brains of schizophrenic patients. These individuals are consistently engaged in tobacco smoking and nicotine is thought to alleviate negative behavioral symptoms or cognitive alterations. In mouse brain, nicotine has been shown to reduce GAD67 promoter methylation and increase its transcription. We assessed the effects of administration of nicotine (1 mg/kg s.c.) for 6 days, in male mice heterozygous for reelin (HRM), a putative model for symptoms related to schizophrenia. Expression of reelin, GAD67 and brain-derived neurotrophic factor (BDNF) was measured in different brain areas. RNA expression analysis evidenced genotype-related changes, with a marked reduction in reelin and GAD67 gene expression in prefrontal cortex, hippocampus, cerebellum, and striatum from HRM. Nicotine treatment selectively reversed the HRM-related phenotype in most brain areas and increased BDNF gene expression in cortex and hippocampus of both genotypes. Locomotor performance in their home cage revealed that HRM subjects were characterized by general hyperactivity; with nicotine administration restoring WT-like levels of locomotion. These findings are interpreted within the hypothesis of pre-existing vulnerability (based on haploinsufficiency of reelin) to brain and behavioral disorders and regulative effects associated with nicotine exposure
One-carbon metabolism and Alzheimer's disease: is it all a methylation matter?
No full textThe sporadic form of Alzheimer disease, late onset Alzheimer's disease (LOAD), is a multifactorial disease; a strong link between nutritional and genetic factors with normal aging and dementia is supported by studies on nutrition, metabolism, and neurodegeneration. Specifically, the involvement of homocysteine (HCY) and its dietary determinants (vitamins B6, B12, and folate, besides methionine) in dementia has been a topic of intense investigation. In this Commentary we would like to highlight the role of 1-carbon metabolism in epigenetics and Alzheimer's disease and evidence the coinvolvement of this metabolism in amyloid and tau pathways. (C) 2011 Elsevier Inc. All rights reserved
Systematic multistep extraction process for the total valorization of fiber fractions from fruit seeds
No full textPSEN1 promoter demethylation in hyperhomocysteinemic TgCRND8 mice is the culprit, not the consequence.
No full textIn recent years, in parallel with the growing awareness of the multifactorial nature of Late Onset Alzheimer's Disease, the possibility that epigenetic mechanisms could be involved in the onset and/or progression of the pathology assumed an increasingly intriguing and leading role in Alzheimer's research. Today, many scientific reports indicate the existence of an epigenetic drift during ageing, in particular in Alzheimer's subjects. At the same time, experimental evidences are provided with the aim to demonstrate the causative or consequential role of epigenetic mechanisms. Our research group was involved in the last ten years in studying DNA methylation, the main epigenetic modification, in relationship to altered one-carbon metabolism (namely high homocysteine and low B vitamins levels), in Alzheimer's experimental models. Our previous findings about the demethylation of Presenilin1 gene promoter in nutritionally-induced hyperhomocysteinemia in a transgenic mouse model clearly demonstrated that Presenilin1 is regulated by DNA methylation. One of the open questions raised by our studies was if the observed demethylation was solely due to the induced imbalance of one-carbon metabolism or could be a response to the massive deposition of amyloid plaques in transgenic mice. Here we analyzed old (10 months) mice under standard diet in order to evidence possible changes in Presenilin1 promoter methylation in transgenic (TgCRND8 mice, carrying a double-mutated human APP transgene) vs. wt mice (129Sv) after prolonged exposure to amyloid. We found no differences in Presenilin1 methylation despite a slight increase in gene expression; these results suggest that amyloid production is not responsible for Presenilin1 demethylation in TgCRND8 mice brain
A reassessment of semiquantitative analytical procedures for DNA methylation: Comparison of bisulfite- and HpaII polymerase-chain-reaction-based methods
No full textTwo techniques in particular are used to study site-specific DNA methylation: genomic sequencing after bisulfite modification and polymerase chain reaction after digestion by a methylation-sensitive endonuclease (usually HpaII). Only the former methodology assesses the methylation status of all the cytosine residues in the DNA sequence, but it is so complex and time consuming that the latter procedure, though limited to the restriction sites recognized by the endonucleasets) used, is often preferred at least for a first analysis. In this work we investigate differences between these two techniques in the assessment of DNA methylation and offer some suggestions on how to avoid uncorrected results. Although there is substantial accordance in the results obtained using these different techniques, we observed a general overestimate for methylation levels above 30% and a general underestimate for methylation levels below this value using the HpaII/ PCR technique in the study of methylation of the 5'-flanking region of the mouse myogenin gene in cultured muscle cells and mouse tissues. (c) 2005 Elsevier Inc. All rights reserved
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