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.

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.

Although the prevalence of obesity is increasing in most countries, partially due to ubiquitous exposure to energy dense foods, not everyone exposed to the current obesogenic environment shows unhealthy weight gain. This suggests that there are marked differences in genetic factors that increase vulnerability for excess weight gain. Indeed, evidence suggests that 40 to 70% of variance in unhealthy weight gain can be attributed to individual genetic variations. Moreover, emerging data imply that genetic vulnerability factors interact with environment risk, which is referred to as an epigenetic process.Whereas most scholars consider obesity to be a disorder that results from the interaction between lifestyle and genetic factors, its origin is complex, poorly understood, and extent treatments are typically ineffective. Like any other aspect of science, our knowledge about the genetic basis of obesity is under constant revision. The current paper provides a review on the origins, mechanisms, evolutionary explanation, prevention and treatment based on genotyping.