Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations

Background: Heterozygous mutations in OPA1 are a common cause of autosomal dominant optic atrophy, sometimes associated with extra-ocular manifestations. Few cases harboring compound heterozygous OPA1 mutations have been described manifesting complex neurodegenerative disorders in addition to optic atrophy. Results: We report here three patients: one boy showing an early-onset mitochondrial disorder with hypotonia, ataxia and neuropathy that was severely progressive, leading to early death because of multiorgan failure; two unrelated sporadic girls manifesting a spastic ataxic syndrome associated with peripheral neuropathy and, only in one, optic atrophy. Using a targeted resequencing of 132 genes associated with mitochondrial disorders, in two probands we found compound heterozygous mutations in OPA1: in the first a 5 nucleotide deletion, causing a frameshift and insertion of a premature stop codon (p.Ser64Asnfs*7), and a missense change (p.Ile437Met), which has recently been reported to have clinical impact; in the second, a novel missense change (p.Val988Phe) co-occurred with the p.Ile437Met substitution. In the third patient a homozygous mutation, c.1180G > A (p.Ala394Thr) in OPA1 was detected by a trio-based whole exome sequencing approach. One of the patients presented also variants in mitochondrial DNA that may have contributed to the peculiar phenotype. The deleterious effect of the identified missense changes was experimentally validated in yeast model. OPA1 level was reduced in available patients\u2019 biological samples, and a clearly fragmented mitochondrial network was observed in patients\u2019 fibroblasts. Conclusions: This report provides evidence that bi-allelic OPA1 mutations may lead to complex and severe multi-system recessive mitochondrial disorders, where optic atrophy might not represent the main feature

Reduction in the levels of CoQ biosynthetic proteins is related to an increase in lifespan without evidence of hepatic mitohormesis

Mitohormesis is an adaptive response induced by a mild mitochondrial stress that promotes longevity and metabolic health in different organisms. This mechanism has been proposed as the cause of the increase in the survival in Coq7+/− (Mclk1+/−) mice, which show hepatic reduction of COQ7, early mitochondrial dysfunction and increased oxidative stress. Our study shows that the lack of COQ9 in Coq9Q95X mice triggers the reduction of COQ7, COQ6 and COQ5, which results in an increase in life expectancy. However, our results reveal that the hepatic CoQ levels are not decreased and, therefore, neither mitochondrial dysfunction or increased oxidative stress are observed in liver of Coq9Q95X mice. These data point out the tissue specific differences in CoQ biosynthesis. Moreover, our results suggest that the effect of reduced levels of COQ7 on the increased survival in Coq9Q95X mice may be due to mitochondrial mechanisms in non-liver tissues or to other unknown mechanisms.This work was supported by grants from Ministerio de Economía Competitividad, Spain, and the ERDF (Grant Number SAF2015-65786-R), from the Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (grant number P10-CTS-6133) and from the University of Granada (grant reference “UNETE”, UCE-PP2017-06). AHG is a “FPU fellow” from the Ministerio de Educación Cultura y Deporte, Spain. MLS was a predoctoral fellow from the Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía. LCL was supported by the “Ramón y Cajal” National Programme, Ministerio de Economía y Competitividad, Spain (RYC-2011-07643)

Cultura política e valores de cidadania na Região Metropolitana de São Paulo

O presente artigo tem como objetivo apresentar uma caracterização da cultura política na Região Metropolitana de São Paulo, analisando atitudes e percepções em torno do sistema político; formas de exercício de cidadania e disponibilidade para o associativismo e ação política. Discute duas hipóteses concorrentes, não excludentes: 1) a clássica interrogação de natureza sociológica da relação entre o contexto socioeconômico e urbano e a cultura política e 2) a consideração de tal processo como fortemente influenciado pela história política local e sua conexão com o nacional. Privilegia a experiência política dos cidadãos como variável independente em relação à cultura política e que se apresenta uma causação cruzada entre o marco institucional e os pressupostos pelos quais os agentes formulam suas preferências.The aim of this present article is to make a characterization of the political culture in the metropolitan region of São Paulo, by examining attitudes and perceptions about the political system, forms of citizenship and availability for the associations and political action. It discusses two competing hypothesis, but not excluded: 1) The classic question of a sociological nature of the relationship between socioeconomic context and urban culture and politics, and 2) the consideration of this process as influenced by local and national history and its connections. It emphasizes the political experience of citizens as independent variable in relation to political culture and that presents a causation between the cross-institutional framework and the assumption by which agents formulate their preferences

Sociedade civil e Estado no Brasil: da autonomia à interdependência política

O conceito de sociedade civil é bastante contestado no seu uso e na sua capacidade de explicação analítica. Reelaborado na teoria democrática nos anos 1990, ele tem sido bastante utilizado no Brasil em diferentes acepções. Alguns autores defendem o seu uso, tal como estabelecido na sociologia-política norte-americana (Cohen e Arato) enquanto outros criticam a ideia da autonomia social a ele inerente. Neste artigo, descrevo o surgimento da sociedade civil no Brasil durante os anos setenta e analiso suas principais áreas de atuação durante sua primeira fase. Analiso também uma segunda fase de interação entre Estado e sociedade civil, mostrando a existência de uma interdependência entre ambos.The concept of civil society is essentially contested in its capacity to explain modern societies. It has been re-elaborated during the early nineties and in its renewed version has been employed in Brazil. A few authors defend its analytical use within the new anglo-saxon model provided by Cohen and Arato whereas other authors criticized the idea of social autonomy. In this article I will describe the emergence of civil society in Brazil during the late seventies and will approach its main area of social action during this first stage. I will also approach a second phase in civil society organization in which it moved to a strategy of inter-dependency with the state