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- Editorial: Advanced (gene and cell) therapies for central nervous system applicationsPublication . Mendonça, Liliana; Webster, Christopher; Boltze, Johannes; Nóbrega, ClévioAdvanced 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. Nine papers were accepted and published in this Research Topic, from which four described original research data, two papers were reviews and two mini reviews, and one paper focused on hypothesis and theory. In the paper Administration of Variants AAV-PHP.B and AAV-PHP.eB on Brain Transduction in Adult Rhesus Macaques (Arotcarena et al.), presented new data on the biodistribution and CNS transduction efficiencies after lumbar intrathecal bolus delivery of identical doses of either AAV-PH.B:CAG-EGFP or AAV-PHP.eB:CAG-EGFP in rhesus macaque monkeys.
- Unraveling the role of ataxin-2 in metabolismPublication . Carmo-Silva, Sara; Nóbrega, Clévio; de Almeida, Luís Pereira; Cavadas, CláudiaAtaxin-2 is a polyglutamine protein implicated in several biological processes such as RNA metabolism and cytoskeleton reorganization. Ataxin-2 is highly expressed in various tissues including the hypothalamus, a brain region that controls food intake and energy balance. Ataxin-2 expression is influenced by nutritional status. Emerging studies discussed here now show that ataxin-2 deficiency correlates with insulin resistance and dyslipidemia, an action mediated via the mTOR pathway, suggesting that ataxin-2 might play key roles in metabolic homeostasis including body weight regulation, insulin sensitivity, and cellular stress responses. In this review we also discuss the relevance of ataxin-2 in the hypothalamic regulation of energy balance, and its potential as a therapeutic target in metabolic disorders such as obesity.
- Restoring brain cholesterol turnover improves autophagy and has therapeutic potential in mouse models of spinocerebellar ataxiaPublication . Nóbrega, Clévio; Mendonca, Liliana; Marcelo, Adriana; Lamaziere, Antonin; Tome, Sandra; Despres, Gaetan; Matos, Carlos A; Mechmet, Fatich; Langui, Dominique; den Dunnen, Wilfred; de Almeida, Luis Pereira; Cartier, Nathalie; Alves, SandroSpinocerebellar ataxias (SCAs) are devastating neurodegenerative disorders for which no curative or preventive therapies are available. Deregulation of brain cholesterol metabolism and impaired brain cholesterol turnover have been associated with several neurodegenerative diseases. SCA3 or Machado-Joseph disease (MJD) is the most prevalent ataxia worldwide. We show that cholesterol 24-hydroxylase (CYP46A1), the key enzyme allowing efflux of brain cholesterol and activating brain cholesterol turnover, is decreased in cerebellar extracts from SCA3 patients and SCA3 mice. We investigated whether reinstating CYP46A1 expression would improve the disease phenotype of SCA3 mouse models. We show that administration of adeno-associated viral vectors encoding CYP46A1 to a lentiviral-based SCA3 mouse model reduces mutant ataxin-3 accumulation, which is a hallmark of SCA3, and preserves neuronal markers. In a transgenic SCA3 model with a severe motor phenotype we confirm that cerebellar delivery of AAVrh10-CYP46A1 is strongly neuroprotective in adult mice with established pathology. CYP46A1 significantly decreases ataxin-3 protein aggregation, alleviates motor impairments and improves SCA3-associated neuropathology. In particular, improvement in Purkinje cell number and reduction of cerebellar atrophy are observed in AAVrh10-CYP46A1-treated mice. Conversely, we show that knocking-down CYP46A1 in normal mouse brain impairs cholesterol metabolism, induces motor deficits and produces strong neurodegeneration with impairment of the endosomal-lysosomal pathway, a phenotype closely resembling that of SCA3. Remarkably, we demonstrate for the first time both in vitro, in a SCA3 cellular model, and in vivo, in mouse brain, that CYP46A1 activates autophagy, which is impaired in SCA3, leading to decreased mutant ataxin-3 deposition. More broadly, we show that the beneficial effect of CYP46A1 is also observed with mutant ataxin-2 aggregates. Altogether, our results confirm a pivotal role for CYP46A1 and brain cholesterol metabolism in neuronal function, pointing to a key contribution of the neuronal cholesterol pathway in mechanisms mediating clearance of aggregate-prone proteins. This study identifies CYP46A1 as a relevant therapeutic target not only for SCA3 but also for other SCAs.
- The stress granule protein G3BP1 alleviates spinocerebellar ataxia-associated deficitsPublication . Koppenol, Rebekah; Conceição, André; Afonso, Inês T.; Afonso-Reis, Ricardo; Costa, Rafael G; Tomé, Sandra; Teixeira, Diogo; Pinto-da-Silva, Joana; Codêsso, José Miguel; Brito, David V.C.; Mendonça, Liliana; Marcelo, Adriana; Pereira de Almeida, Luís; Matos, Carlos A; Nóbrega, ClévioKoppenol et al. show that overexpression of G3BP1 in cell models of SCA2 and SCA3 leads to a reduction in ataxin-2 and ataxin-3 aggregation. G3BP1 lentiviral delivery reduces motor deficits and neuropathology in preclinical models, suggesting that G3BP1 may be a potential therapeutic target for polyQ disorders. Polyglutamine diseases are a group of neurodegenerative disorders caused by an abnormal expansion of CAG repeat tracts in the codifying regions of nine, otherwise unrelated, genes. While the protein products of these genes are suggested to play diverse cellular roles, the pathogenic mutant proteins bearing an expanded polyglutamine sequence share a tendency to self-assemble, aggregate and engage in abnormal molecular interactions. Understanding the shared paths that link polyglutamine protein expansion to the nervous system dysfunction and the degeneration that takes place in these disorders is instrumental to the identification of targets for therapeutic intervention. Among polyglutamine diseases, spinocerebellar ataxias (SCAs) share many common aspects, including the fact that they involve dysfunction of the cerebellum, resulting in ataxia. Our work aimed at exploring a putative new therapeutic target for the two forms of SCA with higher worldwide prevalence, SCA type 2 (SCA2) and type 3 (SCA3), which are caused by expanded forms of ataxin-2 (ATXN2) and ataxin-3 (ATXN3), respectively. The pathophysiology of polyglutamine diseases has been described to involve an inability to properly respond to cell stress. We evaluated the ability of GTPase-activating protein-binding protein 1 (G3BP1), an RNA-binding protein involved in RNA metabolism regulation and stress responses, to counteract SCA2 and SCA3 pathology, using both in vitro and in vivo disease models. Our results indicate that G3BP1 overexpression in cell models leads to a reduction of ATXN2 and ATXN3 aggregation, associated with a decrease in protein expression. This protective effect of G3BP1 against polyglutamine protein aggregation was reinforced by the fact that silencing G3bp1 in the mouse brain increases human expanded ATXN2 and ATXN3 aggregation. Moreover, a decrease of G3BP1 levels was detected in cells derived from patients with SCA2 and SCA3, suggesting that G3BP1 function is compromised in the context of these diseases. In lentiviral mouse models of SCA2 and SCA3, G3BP1 overexpression not only decreased protein aggregation but also contributed to the preservation of neuronal cells. Finally, in an SCA3 transgenic mouse model with a severe ataxic phenotype, G3BP1 lentiviral delivery to the cerebellum led to amelioration of several motor behavioural deficits. Overall, our results indicate that a decrease in G3BP1 levels may be a contributing factor to SCA2 and SCA3 pathophysiology, and that administration of this protein through viral vector-mediated delivery may constitute a putative approach to therapy for these diseases, and possibly other polyglutamine disorders.
- Lipoprotein metabolism, protein aggregation, and Alzheimer’s Disease: A literature reviewPublication . Grao-Cruces, Elena; Claro-Cala, Carmen M.; Montserrat-de la Paz, Sergio; Nóbrega, ClévioAlzheimer’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.
- PolyQ database—an integrated database on polyglutamine diseasesPublication . Estevam, Bernardo; Matos, Carlos A; Nóbrega, ClévioPolyglutamine (polyQ) diseases are neurodegenerative disorders caused by abnormally expanded Cytosine, Adenine, Guanine (CAG) triplet repeat sequences in the coding region of otherwise unrelated genes. Until now, nine different polyQ diseases have been described: Huntington's disease, dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy and six types of spinocerebellar ataxias-1, 2, 3, 6, 7 and 17. The pathogenic expansion translates into an aberrant tract of glutamines in the encoded proteins, compromising several cellular functions and biological processes. There is currently no cure available for the progressive neurodegenerative disorders caused by the ensuing cytotoxic alterations. Although each disease is considered rare, polyQ diseases constitute the largest group of monogenic neurodegenerative disorders. Information about these disorders is scattered among several books, articles and general databases, hindering exploration by students and researchers, but also by patients and their families. Therefore, we aimed to develop a free online database to fill this gap, by centralizing relevant available information. The PolyQ Database is a platform that focuses on all nine polyQ diseases and offers information about topics that are pertinent for scientists, clinicians and the general public, including epidemiology, the characteristics of the causative genes and the codified proteins, the pathophysiology of the diseases and the main clinical manifestations. The database is available at https://polyq.pt/, and it is the first of its kind, focusing exclusively on this group of rare diseases. The database was conceived to be continuously updated and allow incorporation and dissemination of the latest information on polyQ diseases.
- ULK overexpression mitigates motor deficits and neuropathology in mouse models of Machado-Joseph diseasePublication . Vasconcelos-Ferreira, Ana; Martins, Inês Morgado; Lobo, Diana; Pereira, Dina; Lopes, Miguel M.; Faro, Rosário; Lopes, Sara M.; Verbeek, Dineke; Schmidt, Thorsten; Nóbrega, Clévio; Pereira de Almeida, LuísMachado-Joseph disease (MJD) is a fatal neurodegenerative disorder clinically characterized by prominent ataxia. It is caused by an expansion of a CAG trinucleotide in ATXN3, translating into an expanded polyglutamine (polyQ) tract in the ATXN3 protein, that becomes prone to misfolding and aggregation. The pathogenesis of the disease has been associated with the dysfunction of several cellular mechanisms, including autophagy and transcription regulation. In this study, we investigated the transcriptional modifications of the autophagy pathway in models of MJD and assessed whether modulating the levels of the affected autophagy-associated transcripts (AATs) would alleviate MJD-associated pathology. Our results show that autophagy is impaired at the transcriptional level in phagy activating kinase 1 and 2 (ULK1 and ULK2), two homologs involved in autophagy induction. Reinstating ULK1/2 levels by adeno-associated virus (AAV)-mediated gene transfer significantly improved motor performance while preventing in vitro studies showed that the observed positive effects may be mainly attributed to ULK1 activity. This study provides strong evidence of the beneficial effect of overexpression of ders.
- The contribution of genetics and environment to obesityPublication . Albuquerque, David; Nóbrega, Clévio; Manco, Licínio; Padez, CristinaBackground: 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. Sources of data: 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. Areas of agreement: 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. Areas of controversy: 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. Growing points: The integration of multi-omics data enables scientists having a better picture and to elucidate unknown pathways contributing to obesity. Areas timely for developing research: 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.
- Machado-Joseph disease: from pathogenic mechanisms to therapeutic strategiesPublication . Nóbrega, Clévio; Matos, C. A.; Carmo-Silva, S.; Tome, S.; Mendoca, L.; Almeida, Luis Pereira de; Marcelo, A.
- The autophagy‐enhancing drug carbamazepine improves neuropathology and motor impairment in mouse models of Machado–Joseph diseasePublication . Vasconcelos‐Ferreira, Ana; Carmo‐Silva, Sara; Codêsso, José Miguel; Silva, Patrick; Martinez, Alberto Rolim Muro; França Jr, Marcondes Cavalcante; Nóbrega, Clévio; Pereira de Almeida, LuísAims Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), is the most common autosomal dominantly-inherited ataxia worldwide and is characterised by the accumulation of mutant ataxin-3 (mutATXN3) in different brain regions, leading to neurodegeneration. Currently, there are no available treatments able to block disease progression. In this study, we investigated whether carbamazepine (CBZ) would activate autophagy and mitigate MJD pathology. Methods The autophagy-enhancing activity of CBZ and its effects on clearance of mutATXN3 were evaluated using in vitro and in vivo models of MJD. To investigate the optimal treatment regimen, a daily or intermittent CBZ administration was applied to MJD transgenic mice expressing a truncated human ATXN3 with 69 glutamine repeats. Motor behaviour tests and immunohistology was performed to access the alleviation of MJD-associated motor deficits and neuropathology. A retrospective study was conducted to evaluate the CBZ effect in MJD patients. Results We found that CBZ promoted the activation of autophagy and the degradation of mutATXN3 in MJD models upon short or intermittent, but not daily prolonged, treatment regimens. CBZ up-regulated autophagy through activation of AMPK, which was dependent on the myo-inositol levels. In addition, intermittent CBZ treatment improved motor performance, as well as prevented neuropathology in MJD transgenic mice. However, in patients, no evident differences in SARA scale were found, which was not unexpected given the small number of patients included in the study. Conclusions Our data support the autophagy-enhancing activity of CBZ in the brain and suggest this pharmacological approach as a promising therapy for MJD and other polyglutamine disorders.