On the role of RNA binding proteins in polyglutamine diseases: from pathogenesis to therapeutics

Polyglutamine (polyQ) diseases are a group of different neurodegenerative disorders characterized by an abnormal expansion of the trinucleotide cytosine-adenine-guanine (CAG) within coding regions of each disease-associated gene. The abnormal expansion translates into a protein bearing an abnormally long tract of glutamines. The expanded proteins are prone to aggregate, promote aberrant interaction with other proteins and mRNAs and contribute to cellular pathway disruption (Matos et al., 2019). To date, nine different polyQ diseases are described, including among others, Huntington’s disease, and six different spinocerebellar ataxias (SCA). Patients affected by polyQ diseases, suffer a myriad of motor symptoms that include ataxia, dysphagia, tremors, dysarthria, and even dementia. Unfortunately, there is no cure nor treatment able to delay the disease and patients rely only on symptomatic and supportive treatments culminating in premature death (Takahashi et al., 2010).info:eu-repo/semantics/publishedVersio

A multilocus comparative study of nucleotide variation in Drosophila madeirensis and the close relative D. subobscura: insights into the speciation process of D. madeirensis

O estudo da divergência entre espécies relacionadas, utilizando dados de vários loci é uma das formas de estudar a especiação e permite distinguir as forças que actuam em todo o genoma daquelas, como por exemplo a selecção natural, que afectam apenas os loci individualmente. Assim sendo, um dos grandes objectivos deste trabalho foi estudar a história da divergência entre duas espécies relacionadas, Drosophila madeirensis e D. subobscura , utilizando dados de sequências de DNA. O polimorfismo das inversões cromossómicas é uma característica comum do genoma do género Drosophila , no qual cerca de 60% das espécies são polimórficas para as inversões pericêntricas em populações naturais. O outro grande objectivo deste trabalho foi estudar o nível de variação nucleotídica em duas diferentes ordenações do cromossoma X de populações de D. subobscura (A2 e Ast). Assim, a análise da variação nucleotídica ao longo da inversão pode indicar o papel desempenhado pela selecção natural na formação e manutenção dos polimorfismos cromossómicos. Para atingir estes dois principais objectivos foram estudadas cinco regiões (que se distribuíam ao longo da inversão A2) do cromossoma X. De uma forma geral, o nível de polimorfismo nucleotídico encontrado foi similar nas duas espécies, apesar de D. madeirensis ser uma espécie endémica da ilha da Madeira e as populações de D. subobscura estudadas serem também insulares, e por tal se espera que possuam um tamanho populacional efectivo pequeno. Estimou-se o tempo de divergência entre D. subobscura e D. madeirensis em 640.000 e 1.400.000 anos e o modelo de isolamento sem fluxo génico após a divergência como causa de especiação não foi rejeitado. Em relação ao estudo das ordenações cromossómicas de D. subobscura , verificou-se que existe uma grande diferenciação genética em todas as regiões estudadas entre as duas ordenações. Os dados apontam para a existência de fenómenos de conversão génica e pouca evidência de troca de material genético na parte central da inversão.An approach to analyze the genetic changes that occur in populations during speciation is to examine the level and pattern of DNA sequence variation in species that recently shared a common ancestor. This approach becomes even more informative when data from multiple loci are available and thus they can be used to distinguish forces that act on all genes from those, like natural selection or gene flow, that affect individual loci. Therefore, one of the main goals of this study was shed some light into speciation divergence process between D. subobscura and D. madeirensis , using data from five gene regions of X chromosome. Chromosomal inversion polymorphism is a common feature of the genome in the Drosophila genus. About 60% of the Drosophila species are polymorphic for paracentric inversions in natural populations. D. subobscura is a species with a very rich inversion polymorphism, thus, another objective of this study was to analyze the levels of nucleotide variation in two different chromosomal arrangements of this species: A2 and Ast. The levels of nucleotide polymorphism found were very similar between the two species, although D. madeirensis is expected to have a much lower effective population size. A divergence process in allopatry without gene flow could be a likely explanation for the speciation between D. madeirensis and D. subobscura , as the isolation model without migration was not rejected. A strong genetic differentiation in all studied regions was detected between the two chromosomal arrangements of D. subobscura , and evidence of gene conversion was also detected. These data, with those previously reported for the O3 inversion, if extended to other inversions of D. subobscura might indicate that the genome of this species is highly structured

Current status of gene therapy research in polyglutamine spinocerebellar ataxias

Polyglutamine spinocerebellar ataxias (PolyQ SCAs) are a group of 6 rare autosomal dominant diseases, which arise from an abnormal CAG repeat expansion in the coding region of their causative gene. These neurodegenerative ataxic disorders are characterized by progressive cerebellar degeneration, which translates into progressive ataxia, the main clinical feature, often accompanied by oculomotor deficits and dysarthria. Currently, PolyQ SCAs treatment is limited only to symptomatic mitigation, and no therapy is available to stop or delay the disease progression, which culminates with death. Over the last years, many promising gene therapy approaches were investigated in preclinical studies and could lead to a future treatment to stop or delay the disease development. Here, we summed up the most promising of these therapies, categorizing them in gene augmentation therapy, gene silencing strategies, and gene edition approaches. While several of the reviewed strategies are promising, there is still a gap from the preclinical results obtained and their translation to clinical studies. However, there is an increase in the number of approved gene therapies, as well as a constant development in their safety and efficacy profiles. Thus, it is expected that in a near future some of the promising strategies reviewed here could be tested in a clinical setting and if successful provide hope for SCAs patients.Foundation (FCT) project (ALG-01-0145-FEDER-29480)info:eu-repo/semantics/publishedVersio

Editorial: Global excellence in gene and cell therapy : Europe

Gene therapy changes protein expression in cells through the insertion of genes and/or gene expression-modulating tools, including gene editing. It can be used in the treatment of a variety of diseases, including genetic disorders, by reducing the levels of disease-causing proteins or by increasing the expression of missing or protective proteins. Cell therapy by the transplantation of cells or tissues aims to repair, regenerate, or replace a specific cell population and/or tissue to reestablish the physiological function performed by the cells/tissues to replace. In this line, Global Excellence in the Gene and Cell Therapy: Europe Research Topic was launched with the goal of highlighting the latest advancements in Gene and Cell Therapy field and reflecting on the future challenges faced by researchers across Europe

RNA Interference Applications for Machado-Joseph Disease

Machado-Joseph disease (MJD), also named spinocerebellar ataxia type 3 (SCA3), is a dominantly inherited neurodegenerative disease caused by abnormal CAG expansions in MJD1 gene, which translate to an overexpanded tract of glutamines in the ataxin-3 (ATXN3) protein. Since the identification of the causative gene, a huge effort was made toward the development of animal models for MJD/SCA3, to increase the understanding of the molecular mechanisms underpinning disease pathogenesis, and to develop therapeutic strategies for the disease. Nevertheless, until now there are no therapies available capable of stopping or delaying the disease progression, which culminates with the death of the patients. Therefore, there is an urgent unmet need for therapeutic solutions, for which gene therapy stands out. The RNA interference (RNAi) mechanism discovery allowed the identification of small RNA molecules with the ability to regulate gene expression. For gene therapy, RNAi provided a way to silence mutant genes, which are particularly useful in dominantly inherited diseases. In the last years, several studies have focused on using RNAi molecules to target mutant ATXN3. The results showed that this could be an efficient and safe strategy for modifying MJD/SCA3 progression. Now, an additional effort must be done to translate these results into clinical trials

Editorial: Advanced (gene and cell) therapies for central nervous system applications

Advanced therapies as defined by the European Medicines Agency (EMA) comprises strategies involving gene therapy, cell therapy, and tissue engineering. Overall, these strategies offer a wide range of possibilities to treat and cure diseases, including those affecting the central nervous system (CNS). In this line, Advanced (Gene and Cell) Therapies for Central Nervous System Applications Research Topic was intended to provide a platform for researchers to publish their findings, contributing to the continuous advance of this research area

Mutant Ataxin-2 expression in aged animals aggravates neuropathological features associated with Spinocerebellar Ataxia type 2

Spinocerebellar ataxia type 2 (SCA2) is a rare autosomal, dominantly inherited disease, in which the affected individuals have a disease onset around their third life decade. The molecular mechanisms underlying SCA2 are not yet completely understood, for which we hypothesize that aging plays a role in SCA2 molecular pathogenesis. In this study, we performed a striatal injection of mutant ataxin-2 mediated by lentiviral vectors, in young and aged animals. Twelve weeks post-injection, we analyzed the striatum for SCA2 neuropathological features and specific aging hallmarks. Our results show that aged animals had a higher number of mutant ataxin-2 aggregates and more neuronal marker loss, compared to young animals. Apoptosis markers, cleaved caspase-3, and cresyl violet staining also indicated increased neuronal death in the aged animal group. Additionally, mRNA levels of microtubule-associated protein 1 light-chain 3B (LC3) and sequestosome-1 (SQSTM1/p62) were altered in the aged animal group, suggesting autophagic pathway dysfunction. This work provides evidence that aged animals injected with expanded ataxin-2 had aggravated SCA2 disease phenotype, suggesting that aging plays an important role in SCA2 disease onset and disease progression.info:eu-repo/semantics/publishedVersio

Lipoprotein metabolism, protein aggregation, and Alzheimer’s Disease: A literature review

Alzheimer’s disease (AD) is the most common form of dementia. The physiopathology of AD is well described by the presence of two neuropathological features: amyloid plaques and tau neurofibrillary tangles. In the last decade, neuroinflammation and cellular stress have gained importance as key factors in the development and pathology of AD. Chronic cellular stress occurs in degenerating neurons. Stress Granules (SGs) are nonmembranous organelles formed as a response to stress, with a protective role; however, SGs have been noted to turn into pathological and neurotoxic features when stress is chronic, and they are related to an increased tau aggregation. On the other hand, correct lipid metabolism is essential to good function of the brain; apolipoproteins are highly associated with risk of AD, and impaired cholesterol efflux and lipid transport are associated with an increased risk of AD. In this review, we provide an insight into the relationship between cellular stress, SGs, protein aggregation, and lipid metabolism in AD.info:eu-repo/semantics/publishedVersio

From the molecular hallmarks to motor behavior: characterization of a new transgenic mouse model for spinocerebellar ataxia type 2

Spinocerebellar ataxia type 2 (SCA2) is a rare disease with no cure, and therefore patients depend on symptomatic and supportive treatments. It is a highly debilitating disease affecting predominantly the brain with symptoms that include motor and coordination impairment. SCA2 is caused by an abnormal expansion of the CAG triplet in the coding region of the ATXN2 gene. When it has above 33 CAG repeats, it originates a protein with an abnormally expanded glutamine tract. The mutant protein impairs several cellular functions, leading to neuronal degeneration and death. Several rodent models were developed to study the neuropathology and potential therapies for SCA2. However, most of them fail to mimic a complete SCA2 phenotype, taking too long to develop diseaserelated symptoms or failing to display neuronal-associated deficits.info:eu-repo/semantics/publishedVersio