Aim
The ‐13910C>T single nucleotide polymorphism located upstream of the lactase gene (LCT) was found tightly associated with lactase persistence in European populations. Recently, it was also ...associated with body mass index (BMI) and obesity in European adults. The aim of this study was to test the association of ‐13910C>T polymorphism with obesity‐related traits and risk of obesity in children.
Methods
We genotyped 580 Portuguese children (6–12‐year‐olds) for the ‐13910C>T polymorphism using TaqMan probes by real‐time PCR. Anthropometric measurements were assessed in all children. Obesity was defined according to the International Obesity Task Force (IOTF) cut‐offs and abdominal obesity using the sex and age‐specific ≥90th waist circumference percentile.
Results
We found indication for an association between the‐13910*T allele and children abdominal obesity (odds ratio OR = 1.41; 95% confidence intervals CI: 1.03–1.94; p = 0.030). Under the dominant model, the indicative association was observed between the LCT‐13910 CT/TT genotypes and abdominal obesity, remaining significant after adjustment for age and gender (OR = 1.65; 95% CI: 1.04–2.60; p = 0.029). No association was detected with the risk of obesity (p = 0.350).
Conclusion
Our results suggest that the ‐13910C>T polymorphism may predispose to abdominal obesity in Portuguese children. The association with BMI or risk of obesity, previously observed in adults, was not confirmed.
Machado-Joseph disease (MJD) or spinocerebellar ataxia 3 (SCA3) is a rare, inherited, monogenic, neurodegenerative disease, and the most common SCA worldwide. MJD/SCA3 causative mutation is an ...abnormal expansion of the triplet CAG at exon 10 within the
gene. The gene encodes for ataxin-3, which is a deubiquitinating protein that is also involved in transcriptional regulation. In normal conditions, the ataxin-3 protein polyglutamine stretch has between 13 and 49 glutamines. However, in MJD/SCA3 patients, the size of the stretch increases from 55 to 87, contributing to abnormal protein conformation, insolubility, and aggregation. The formation of aggregates, which is a hallmark of MJD/SCA3, compromises different cell pathways, leading to an impairment of cell clearance mechanisms, such as autophagy. MJD/SCA3 patients display several signals and symptoms in which the most prominent is ataxia. Neuropathologically, the regions most affected are the cerebellum and the pons. Currently, there are no disease-modifying therapies, and patients rely only on supportive and symptomatic treatments. Due to these facts, there is a huge research effort to develop therapeutic strategies for this incurable disease. This review aims to bring together current state-of-the-art strategies regarding the autophagy pathway in MJD/SCA3, focusing on evidence for its impairment in the disease context and, importantly, its targeting for the development of pharmacological and gene-based therapies.
Stress granules (SGs) are membraneless cell compartments formed in response to different stress stimuli, wherein translation factors, mRNAs, RNA-binding proteins (RBPs) and other proteins coalesce ...together. SGs assembly is crucial for cell survival, since SGs are implicated in the regulation of translation, mRNA storage and stabilization and cell signalling, during stress. One defining feature of SGs is their dynamism, as they are quickly assembled upon stress and then rapidly dispersed after the stress source is no longer present. Recently, SGs dynamics, their components and their functions have begun to be studied in the context of human diseases. Interestingly, the regulated protein self-assembly that mediates SG formation contrasts with the pathological protein aggregation that is a feature of several neurodegenerative diseases. In particular, aberrant protein coalescence is a key feature of polyglutamine (PolyQ) diseases, a group of nine disorders that are caused by an abnormal expansion of PolyQ tract-bearing proteins, which increases the propensity of those proteins to aggregate. Available data concerning the abnormal properties of the mutant PolyQ disease-causing proteins and their involvement in stress response dysregulation strongly suggests an important role for SGs in the pathogenesis of PolyQ disorders. This review aims at discussing the evidence supporting the existence of a link between SGs functionality and PolyQ disorders, by focusing on the biology of SGs and on the way it can be altered in a PolyQ disease context.
Obesity is a global health problem mainly attributed to lifestyle changes such as diet, low physical activity or socioeconomics factors. However, several evidences consistently showed that genetics ...contributes significantly to the weight-gain susceptibility.
A systematic literature search of most relevant original, review and meta-analysis, restricted to English was conducted in PubMed, Web of Science and Google scholar up to May 2017 concerning the contribution of genetics and environmental factors to obesity.
Several evidences suggest that obesogenic environments contribute to the development of an obese phenotype. However, not every individual from the same population, despite sharing the same obesogenic environment, develop obesity.
After more than 10 years of investigation on the genetics of obesity, the variants found associated with obesity represent only 3% of the estimated BMI-heritability, which is around 47-80%. Moreover, genetic factors per se were unable to explain the rapid spread of obesity prevalence.
The integration of multi-omics data enables scientists having a better picture and to elucidate unknown pathways contributing to obesity.
New studies based on case-control or gene candidate approach will be important to identify new variants associated with obesity susceptibility and consequently unveiling its genetic architecture. This will lead to an improvement of our understanding about underlying mechanisms involved in development and origin of the actual obesity epidemic. The integration of several omics will also provide insights about the interplay between genes and environments contributing to the obese phenotype.
Neuropeptide Y (NPY) produced by arcuate nucleus (ARC) neurons has a strong orexigenic effect on target neurons. Hypothalamic NPY levels undergo wide-ranging oscillations during the circadian cycle ...and in response to fasting and peripheral hormones (from 0.25 to 10-fold change). The aim of the present study was to evaluate the impact of a moderate long-term modulation of NPY within the ARC neurons on food consumption, body weight gain and hypothalamic neuropeptides. We achieved a physiological overexpression (3.6-fold increase) and down-regulation (0.5-fold decrease) of NPY in the rat ARC by injection of AAV vectors expressing NPY and synthetic microRNA that target the NPY, respectively. Our work shows that a moderate overexpression of NPY was sufficient to induce diurnal over-feeding, sustained body weight gain and severe obesity in adult rats. Additionally, the circulating levels of leptin were elevated but the immunoreactivity (ir) of ARC neuropeptides was not in accordance (POMC-ir was unchanged and AGRP-ir increased), suggesting a disruption in the ability of ARC neurons to response to peripheral metabolic alterations. Furthermore, a dysfunction in adipocytes phenotype was observed in these obese rats. In addition, moderate down-regulation of NPY did not affect basal feeding or normal body weight gain but the response to food deprivation was compromised since fasting-induced hyperphagia was inhibited and fasting-induced decrease in locomotor activity was absent.These results highlight the importance of the physiological ARC NPY levels oscillations on feeding regulation, fasting response and body weight preservation, and are important for the design of therapeutic interventions for obesity that include the NPY.
It is well-known that obesity is a complex multifactorial and heterogeneous condition with an important genetic component. Recently, major advances in obesity research emerged concerning the ...molecular mechanisms contributing to the obese condition. This review outlines several studies and data concerning the genetics and other important factors in the susceptibility risk to develop obesity. Based in the genetic etiology three main categories of obesity are considered: monogenic, syndromic, and common obesity. For the monogenic forms of obesity, the gene causing the phenotype is clearly identified, whereas for the common obesity the loci architecture underlying the phenotype is still being characterized. Given that, in this review we focus mainly in this obesity form, reviewing loci found until now by genome-wide association studies related with the susceptibility risk to develop obesity. Moreover, we also detail the obesity-related loci identified in children and in different ethnic groups, trying to highlight the complexity of the genetics underlying the common obese phenotype. Importantly, we also focus in the evolutionary hypotheses that have been proposed trying to explain how natural selection favored the spread of genes that increase the risk for an obese phenotype and how this predisposition to obesity evolved. Other factors are important in the obesity condition, and thus, we also discuss the epigenetic mechanisms involved in the susceptibility and development of obesity. Covering all these topics we expect to provide a complete and recent perspective about the underlying mechanisms involved in the development and origin of obesity. Only with a full understanding of the factors and mechanisms contributing to obesity, it will be possible to provide and allow the development of new therapeutic approaches to this condition.
Machado-Joseph disease or spinocerebellar ataxia type 3, the most common dominantly-inherited spinocerebellar ataxia, results from translation of the polyglutamine-expanded and aggregation prone ...ataxin 3 protein. Clinical manifestations include cerebellar ataxia and pyramidal signs and there is no therapy to delay disease progression. Beclin 1, an autophagy-related protein and essential gene for cell survival, is decreased in several neurodegenerative disorders. This study aimed at evaluating if lentiviral-mediated beclin 1 overexpression would rescue motor and neuropathological impairments when administered to pre- and post-symptomatic lentiviral-based and transgenic mouse models of Machado-Joseph disease. Beclin 1-mediated significant improvements in motor coordination, balance and gait with beclin 1-treated mice equilibrating longer periods in the Rotarod and presenting longer and narrower footprints. Furthermore, in agreement with the improvements observed in motor function beclin 1 overexpression prevented neuronal dysfunction and neurodegeneration, decreasing formation of polyglutamine-expanded aggregates, preserving Purkinje cell arborization and immunoreactivity for neuronal markers. These data show that overexpression of beclin 1 in the mouse cerebellum is able to rescue and hinder the progression of motor deficits when administered to pre- and post-symptomatic stages of the disease.
Polyglutamine spinocerebellar ataxias (PolyQ SCAs) represent a group of monogenetic diseases in which the expanded polyglutamine repeats give rise to a mutated protein. The abnormally expanded ...polyglutamine protein produces aggregates and toxic species, causing neuronal dysfunction and neuronal death. The main symptoms of these disorders include progressive ataxia, motor dysfunction, oculomotor impairment, and swallowing problems. Nowadays, the current treatments are restricted to symptomatic alleviation, and no existing therapeutic strategies can reduce or stop the disease progression. Even though the origin of these disorders has been associated with polyglutamine‐induced toxicity, RNA toxicity has recently gained relevance in polyQ SCAs molecular pathogenesis. Therefore, the research's focus on RNA metabolism has been increasing, especially on RNA‐binding proteins (RBPs). The present review summarizes RNA metabolism, exposing the different processes and the main RBPs involved. We also explore the mechanisms by which RBPs are dysregulated in PolyQ SCAs. Finally, possible therapies targeting the RNA metabolism are presented as strategies to reverse neuropathological anomalies and mitigate physical symptoms.
We expose the different roles of RNA‐binding proteins (RBPs) along the RNA metabolism, from transcription to translation. Considering the possible role of RBPs' dysregulation in polyglutamine spinocerebellar ataxias diseases, we present possible therapeutic strategies targeting RBPs, their expression, or the mechanisms in which they are involved. We believe that RBPs might be relevant molecular targets for therapeutics for these disorders.
Machado–Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an incurable disorder, widely regarded as the most common form of spinocerebellar ataxia in the world. MJD/SCA3 ...arises from mutation of the ATXN3 gene, but this simple monogenic cause contrasts with the complexity of the pathogenic mechanisms that are currently admitted to underlie neuronal dysfunction and death. The aberrantly expanded protein product – ataxin‐3 – is known to aggregate and generate toxic species that disrupt several cell systems, including autophagy, proteostasis, transcription, mitochondrial function and signalling. Over the years, research into putative therapeutic approaches has often been devoted to the development of strategies that counteract disease at different stages of cellular pathogenesis. Silencing the pathogenic protein, blocking aggregation, inhibiting toxic proteolytic processing and counteracting dysfunctions of the cellular systems affected have yielded promising ameliorating results in studies with cellular and animal models. The current review analyses the available studies dedicated to the investigation of MJD/SCA3 pathogenesis and the exploration of possible therapeutic strategies, focusing primarily on gene therapy and pharmacological approaches rooted on the molecular and cellular mechanisms of disease.
The complex cascade of molecular and cellular events underlying Machado–Joseph disease, also known as spinocerebellar ataxia type 3 (SCA3), contains several opportunities for therapeutic intervention. Gene therapy and pharmacological approaches aiming at decreasing the formation of toxic ataxin‐3 (atxn3) species or at counteracting the disruption of cellular systems that are crucial for cell function and survival demonstrate promising ameliorating effects in cellular and animal models.
Several studies have reported an association between single nucleotide polymorphisms in the first intron of the FTO gene and body mass index (BMI) or obesity. However, this association has not yet ...been studied among the Portuguese population. This study aims to assess the association of three FTO polymorphisms (rs1861868, rs1421085 and rs9939609) with obesity-related outcomes in a sample of Portuguese children.
We examined a total of 730 children, 256 normal-weight (55.9% girls), 320 overweight (45.3% girls) and 154 obese (53.2% girls), aging from 6 to 12-years-old, recruited randomly from public schools in the central region of Portugal. DNA samples were genotyped for the three polymorphisms by allelic discrimination TaqMan assay. Association of the FTO polymorphisms with several anthropometric traits was investigated. Additionally, we tested association with the risk of obesity using overweight and obese vs. normal-weight children.
We found significant associations of rs9939609 and rs1421085 polymorphisms with weight, BMI, BMI Z-score, waist circumference and hip circumference, even after age and gender adjustment (p<0.05 in all traits). For rs1861868 polymorphism, marginally significant associations were obtained with weight (p = 0.081) and BMI (p = 0.096) after adjustment for age and gender. In case-control studies, both rs9939609 and rs1421085 polymorphisms were significantly associated with obesity (OR 1.97; 95% CI, 1.08-3.59; p = 0.026; OR 2.11; 95% CI, 1.17-3.81; p = 0.013, respectively) but not with overweight (p>0.05). Haplotype analyses identified two combinations (ACA and GCA) associated with a higher risk of obesity (OR 1.53; 95% CI, 1.06-2.22; p = 0.023; OR 1.73; 95% CI, 1.06-2.87; p = 0.030, respectively).
This study provides the first evidence for the association of FTO polymorphisms with anthropometric traits and risk of obesity in Portuguese children.
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