Oxidative Stress in Tauopathies: From Cause to Therapy

Oxidative stress (OS) is the result of an imbalance between the production of reactive oxygen species (ROS) and the antioxidant capacity of cells. Due to its high oxygen demand, the human brain is highly susceptible to OS and, thus, it is not a surprise that OS has emerged as an essential component of the pathophysiology of several neurodegenerative diseases, including tauopathies. Tauopathies are a heterogeneous group of age-related neurodegenerative disorders characterized by the deposition of abnormal tau protein in the affected neurons. With the worldwide population aging, the prevalence of tauopathies is increasing, but effective therapies have not yet been developed. Since OS seems to play a key role in tauopathies, it has been proposed that the use of antioxidants might be beneficial for tau-related neurodegenerative diseases. Although antioxidant therapies looked promising in preclinical studies performed in cellular and animal models, the antioxidant clinical trials performed in tauopathy patients have been disappointing. To develop effective antioxidant therapies, the molecular mechanisms underlying OS in tauopathies should be completely understood. Here, we review the link between OS and tauopathies, emphasizing the causes of OS in these diseases and the role of OS in tau pathogenesis. We also summarize the antioxidant therapies proposed as a potential treatment for tauopathies and discuss why they have not been completely translated to clinical trials. This review aims to provide an integrated perspective of the role of OS and antioxidant therapies in tauopathies. In doing so, we hope to enable a more comprehensive understanding of OS in tauopathies that will positively impact future studies.This study has been funded by the “Instituto de Salud Carlos III” (ISCIII) through the projects CP21_00049, CP20_00007 and PI21_00183 and co-funded by the European Union.S

Heavy metals contaminating the environment of a progressive supranuclear palsy cluster induce tau accumulation and cell death in cultured neurons

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by the presence of intracellular aggregates of tau protein and neuronal loss leading to cognitive and motor impairment. Occurrence is mostly sporadic, but rare family clusters have been described. Although the etiopathology of PSP is unknown, mutations in the MAPT/tau gene and exposure to environmental toxins can increase the risk of PSP. Here, we used cell models to investigate the potential neurotoxic effects of heavy metals enriched in a highly industrialized region in France with a cluster of sporadic PSP cases. We found that iPSC-derived iNeurons from a MAPT mutation carrier tend to be more sensitive to cell death induced by chromium (Cr) and nickel (Ni) exposure than an isogenic control line. We hypothesize that genetic variations may predispose to neurodegeneration induced by those heavy metals. Furthermore, using an SH-SY5Y neuroblastoma cell line, we showed that both heavy metals induce cell death by an apoptotic mechanism. Interestingly, Cr and Ni treatments increased total and phosphorylated tau levels in both cell types, implicating Cr and Ni exposure in tau pathology. Overall, this study suggests that chromium and nickel could contribute to the pathophysiology of tauopathies such as PSP by promoting tau accumulation and neuronal cell death

Comparative evaluation of 11 commercialized rapid diagnostic tests for detecting Trypanosoma cruzi antibodies in serum banks in areas of endemicity and nonendemicity

Chagas disease is one of the main public health issues in Latin America. Increasingly during the past few decades, Trypanosoma cruzi infection has been detected in North America, Europe, and the Western Pacific, mainly as a result of population movement. The limited availability of rapid serological diagnostic tests hinders rapid diagnosis and early treatment in areas of endemicity and nonendemicity. In collaboration with 11 national reference laboratories (NRLs) from different geographical areas, we evaluated the performances of commercialized serological rapid diagnostic tests (RDT) for T. cruzi infection. Eleven commercialized T. cruzi infection RDTs were evaluated on a total of 474 samples extensively tested with at least three different techniques for Chagas disease, maintained at controlled low temperatures, and stored in the serum banks of the 11 NRLs. We measured the sensitivity, specificity, and concordance of each RDT and provided an additional questionnaire to evaluate its ease of use. The selected RDTs in this study were performed under controlled laboratory conditions. Out of the 11 RDTs, we found 8 of them to be useful, with the cassette format favored over the strip. We did not observe significant differences in RDT performances in the different regions. Overall, the performance results were lower than those disclosed by the manufacturers. The results of this evaluation validate the possibility of using RDTs to diagnose Chagas disease, thereby decreasing the time to treatment at a primary health care facility for patients who are willing to be treated. Further studies should be conducted in the laboratory and in the field to confirm these data, expressly to evaluate reproducibility in resource-limited settings, or using whole blood in clinical settings in areas of endemicity and nonendemicity

Inactivation of CDK/pRb Pathway Normalizes Survival Pattern of Lymphoblasts Expressing the FTLD-Progranulin Mutation c.709-1G>A

8 figuras, 2 tablasBackground Mutations in the progranulin (PGRN) gene, leading to haploinsufficiency, cause familial frontotemporal lobar degeneration (FTLD-TDP), although the pathogenic mechanism of PGRN deficit is largely unknown. Allelic loss of PGRN was previously shown to increase the activity of cyclin-dependent kinase (CDK) CDK6/pRb pathway in lymphoblasts expressing the c.709-1G>A PGRN mutation. Since members of the CDK family appear to play a role in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults, we investigated the role of CDK6/pRb in cell survival/death mechanisms following serum deprivation. Methodology/Principal Findings We performed a comparative study of cell viability after serum withdrawal of established lymphoblastoid cell lines from control and carriers of c.709-1G>A PGRN mutation, asymptomatic and FTLD-TDP diagnosed individuals. Our results suggest that the CDK6/pRb pathway is enhanced in the c.709-1G>A bearing lymphoblasts. Apparently, this feature allows PGRN-deficient cells to escape from serum withdrawal-induced apoptosis by decreasing the activity of executive caspases and lowering the dissipation of mitochondrial membrane potential and the release of cytochrome c from the mitochondria. Inhibitors of CDK6 expression levels like sodium butyrate or the CDK6 activity such as PD332991 were able to restore the vulnerability of lymphoblasts from FTLD-TDP patients to trophic factor withdrawal. Conclusion/Significance The use of PGRN-deficient lymphoblasts from FTLD-TDP patients may be a useful model to investigate cell biochemical aspects of this disease. It is suggested that CDK6 could be potentially a therapeutic target for the treatment of the FTLD-TDPThis work has been supported by grants from Ministry of Education and Science (SAF2007-61701, SAF2010-15700, SAF2011-28603), Fundación Eugenio Rodríguez Pascual, and Basque Government (Saiotek program 2008–2009). NE holds a fellowship of the JAE predoctoral program of the CSICPeer reviewe

Hiperplasia adrenal congênita tipo não-clássica (LATE ONSET) em indivíduos fraternos

Introdução: Hiperplasia adrenal congênita (HAC) ocorre por erro inato do metabolismo do cortisol, na conversão de 17-hidroxiprogesterona (17OHP) em 11-deoxicortisol. Mais de 90% dos casos ocorre pela deficiência da 21- hidroxilase (mutação no gene da CYP21). Há 3 formas: Virilizante Simples, Perdedora de Sal e Não-Clássica (NC). Em crianças, 17OHP>82ng/dl sugere HAC-NC, sendo que nas meninas, os sintomas são pubarca precoce, acne, avanço da idade óssea e clitoromegalia; e nos meninos, pubarca precoce, aumento do pênis e acne. Em mulheres, o diagnóstico é feito com 17OHP>200ng/dl, podendo ter irregularidade menstrual, infertilidade e ovários policísticos. Homens normalmente são assintomáticos e diagnosticados em avaliação familial. Objetivo: Relatar caso de HAC-NC em indivíduos fraternos. Metodologia: Irmãos, feminino e masculino, atendidos em ambulatório diagnosticados com HAC-NC. Relato de Caso: Pacientes vistos em épocas diferentes. Irmã, de idade pueril, queixa de início de pubarca, pelos axilares e acne. Aos exames: tiróide, LH, FSH, HGH, IGF, US abdominal normais, 17OHP de 2400ng/dl e idade óssea adiantada em 2 anos. Irmão, de idade pueril, com baixa estatura e pubarca, com exames normais e 17OHP de 374ng/dl. Hipótese diagnóstica: HAC de início tardio (late onset). Conclusão: Recomenda-se avaliação clínica criteriosa em irmãos, considerando a influência genética e tratamento, para garantir uma melhor qualidade de vida

Psoríase pustulosa palmo-plantar de apresentação unilateral

Introdução: Psoríase pustulosa é um subtipo menos comum de psoríase, que pode manifestar de forma generalizada ou localizada. Forma localizada ocorre geralmente de maneira bilateral e simétrica nas regiões das palmas e plantas (Psoríase Pustulosa Palmo-Plantar – PPPP), e quando a erupção das pústulas acontece no leito ungueal e nas extremidades dos dedos, há a acrodermatite de Hallopeau. PPPP é caracterizada por pústulas estéreis nas palmas e plantas com eritema, fissuras e hiperqueratose; além de prurido, queimação ou dor. Pode persistir por anos, com períodos de exacerbação e remissão, sendo de difícil tratamento. Em geral, a PPPP é rara, acometendo principalmente mulheres de meia idade, com associação ao tabagismo. Diagnóstico é feito pelo exame físico e análise anatomopatológica com: paraqueratose, espongiose epidérmica com acúmulo de neutrófilos na epiderme (pústulas espongiformes de Kogoj e microabscessos de Munro). Objetivo: Relatar caso de PPPP, com acometimento unilateral. Metodologia: Paciente atendida em ambulatório com diagnóstico de PPPP unilateral em planta e palma esquerdas. Relato de Caso: Sexo feminino, 55, com queixa de lesão na região plantar e palmar esquerda com eritema, descamação e pequenas pústulas. Análise histopatológica mostrando paraceratose, microabcessos córneos, espongiose e prolongamento das cristas epiteliais; derme com infiltrado inflamatório linfocitário na derme superficial. Hipótese diagnóstica: PPPP unilateral. Conclusão: PPPP é variante clínica incomum da psoríase, de difícil tratamento e que compromete de forma significativa a qualidade de vida. Recomenda-se o manejo individualizado, tendo em vista o diagnóstico precoce e tratamento para garantir a qualidade de vida do paciente

Eflúvio telógeno pós quadro de dengue - relatos de casos

Introdução: Eflúvio telógeno (ET) é uma forma de alopecia difusa caracterizada pelo aumento do número de fios na fase telógena, como resultado de uma mudança anormal no ciclo folicular, podendo ser crônica ou transitória. ET pode ser desencadeado por: febre, cirurgia, drogas, doenças sistêmicas, estresse, entre outros. Não existe explicação definitiva para o fenômeno, mas sabe-se que as alterações aceleram a entrada dos fios da fase anágena para a fase telógena. Geralmente o ET ocorre cerca de 2 a 3 meses após a ocorrência do fato que a gerou. Diagnóstico do ET é difícil pela ausência de sintomas ou características específicas; eventualmente o cabelo pode tornar-se mais fino e apresentar algum grau de rarefação; não há prurido, descamação ou inflamação; o teste de tração leve dos fios pode ser positivo e o tricograma apresentará mais do que 20% de fios telógenos. Tratamento do ET depende do fator desencadeante e seu controle, mas não há tratamento específico para o eflúvio telógeno. Objetivo: Relatar 11 casos de ET após quadro febril-infeccioso de dengue. Metodologia: Pacientes atendidos em ambulatório diagnosticados com ET, no período de junho a agosto de 2015. Resultados: 10 pacientes do sexo feminino e 1 masculino, referiram queixa de queda de cabelo após quadro de dengue, com início da perda dos fios variando de 1 a 5 meses após o quadro infeccioso (5 casos após 1 mês, 1 caso após 2 meses, 1 caso após 3 meses, 3 casos após 4 meses e 1 caso após 1 mês). Conclusão: ET geralmente é uma doença reativa e reversível. Muitas vezes, após um quadro febril-infeccioso, a queda se resolve de forma espontânea, mas causa grande preocupação pela intensidade e rapidez da instalação da queda. Portanto, identificar e corrigir possíveis causas subjacentes e tranquilizar o paciente são os componentes mais importantes no tratamento