Altered lipid metabolism in a Drosophila model of Friedreich’s ataxia

Producción CientíficaFriedreich’s ataxia (FRDA) is the most common form of autosomal recessive ataxia caused by a deficit in the mitochondrial protein frataxin. Although demyelination is a common symptom in FRDA patients, no multicellular model has yet been developed to study the involvement of glial cells in FRDA. Using the recently established RNAi lines for targeted suppression of frataxin in Drosophila, we were able to study the effects of general versus glial-specific frataxin downregulation. In particular, we wanted to study the interplay between lowered frataxin content, lipid accumulation and peroxidation and the consequences of these effects on the sensitivity to oxidative stress and fly fitness. Interestingly, ubiquitous frataxin reduction leads to an increase in fatty acids catalyzing an enhancement of lipid peroxidation levels, elevating the intracellular toxic potential. Specific loss of frataxin in glial cells triggers a similar phenotype which can be visualized by accumulating lipid droplets in glial cells. This phenotype is associated with a reduced lifespan, an increased sensitivity to oxidative insult, neurodegenerative effects and a serious impairment of locomotor activity. These symptoms fit very well with our observation of an increase in intracellular toxicity by lipid peroxides. Interestingly, co-expression of a Drosophila apolipoprotein D ortholog (glial lazarillo) has a strong protective effect in our frataxin models, mainly by controlling the level of lipid peroxidation. Our results clearly support a strong involvement of glial cells and lipid peroxidation in the generation of FRDA-like symptoms.2015-09-1

The DEAR experiment on DAΦNE

DEAR is one of the first experiments at the new DAΦNE Ø-factory at the Laboratori Nazionali di Frascati dell'INFN. The objective of the DEAR experiment is to perform a precision measurement of the strong interaction shifts and widths of the K-series lines in kaonic hydrogen and the first observation of the same quantities in kaonic deuterium. The aim is to obtain a precise determination of the isospin-dependent kaon-nucleon scattering lengths which will represent a breakthrough in KN low-energy phenomenology and will allow us to determine the kaon-nucleon sigma terms. The sigma terms give a direct measurement of chiral symmetry breaking and are connected to the strangeness content of the proton. First results on background measurements with the DEAR NTP setup installed on DAΦNE are reported

Efficient Palladium-Catalyzed Cyclotrimeriza- tion of Arynes: Synthesis of Triphenylenes**

Over the last 15 years much effort has been devoted to the preparation and characterization of transition metal complexes of arynes. [1] Parallel studies on the reactivity of these complexesÐparticularly those of Ti, Zr, As part of a project aimed at the development of new reactions of arynes promoted by metal complexes, here we report on the metal-mediated cyclotrimerization of arynes. These preliminary results show that the reaction proceeds in the presence of catalytic amounts of metal and that it has great potential for the preparation of triphenylenes, which are found at the core of many discotic liquid crystals [9] An example of the formation of triphenylene as side product of a palladium-catalyzed domino reaction has also been reported. [10] However, to the best of our knowledge, efficient preparation of triphenylenes by metalcatalyzed reaction of arynes is without precedent. Development of a catalytic procedure for the trimerization of arynes requires careful selection of the catalyst and the method for generation of the aryne. The catalyst was chosen from among the various metal systems used for trimerization of alkynes; suitable candidates contained metals such as Ni, Co, Pd, and Pt. We decided to carry out the first trials with palladium complexes because they are easy to handle and in general stable. Among the many procedures available for the generation of arynes [9] S

Overexpression of Human and Fly Frataxins in Drosophila Provokes Deleterious Effects at Biochemical, Physiological and Developmental Levels

10 pages, 5 figures. 21779322[PubMed] PMCID: PMC3136927BACKGROUND: Friedreich's ataxia (FA), the most frequent form of inherited ataxias in the Caucasian population, is caused by a reduced expression of frataxin, a highly conserved protein. Model organisms have contributed greatly in the efforts to decipher the function of frataxin; however, the precise function of this protein remains elusive. Overexpression studies are a useful approach to investigate the mechanistic actions of frataxin; however, the existing literature reports contradictory results. To further investigate the effect of frataxin overexpression, we analyzed the consequences of overexpressing human (FXN) and fly (FH) frataxins in Drosophila. METHODOLOGY/PRINCIPAL FINDINGS: We obtained transgenic flies that overexpressed human or fly frataxins in a general pattern and in different tissues using the UAS-GAL4 system. For both frataxins, we observed deleterious effects at the biochemical, histological and behavioral levels. Oxidative stress is a relevant factor in the frataxin overexpression phenotypes. Systemic frataxin overexpression reduces Drosophila viability and impairs the normal embryonic development of muscle and the peripheral nervous system. A reduction in the level of aconitase activity and a decrease in the level of NDUF3 were also observed in the transgenic flies that overexpressed frataxin. Frataxin overexpression in the nervous system reduces life span, impairs locomotor ability and causes brain degeneration. Frataxin aggregation and a misfolding of this protein have been shown not to be the mechanism that is responsible for the phenotypes that have been observed. Nevertheless, the expression of human frataxin rescues the aconitase activity in the fh knockdown mutant. CONCLUSION/SIGNIFICANCE: Our results provide in vivo evidence of a functional equivalence for human and fly frataxins and indicate that the control of frataxin expression is important for treatments that aim to increase frataxin levels.This work was supported by grants from Fondo Investigaciones Sanitarias (ISCIII06- PI0677) and La Fundació la Marató TV3 (exp 101932) of Spain. JVL is supported by the European Friedreich's Ataxia Consortium for Translational Studies. SS is a recipient of a fellowship from Ministerio de Ciencia e Innovación of Spain.Peer reviewe