SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits

Hexanucleotide repeat expansions in the C9ORF72 gene are the commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Expression of repeat transcripts and dipeptide repeat proteins trigger multiple mechanisms of neurotoxicity. How repeat transcripts get exported from the nucleus is unknown. Here, we show that depletion of the nuclear export adaptor SRSF1 prevents neurodegeneration and locomotor deficits in a Drosophila model of C9ORF72-related disease. This intervention suppresses cell death of patient-derived motor neuron and astrocytic-mediated neurotoxicity in co-culture assays. We further demonstrate that either depleting SRSF1 or preventing its interaction with NXF1 specifically inhibits the nuclear export of pathological C9ORF72 transcripts, the production of dipeptide-repeat proteins and alleviates neurotoxicity in Drosophila, patient-derived neurons and neuronal cell models. Taken together, we show that repeat RNA-sequestration of SRSF1 triggers the NXF1-dependent nuclear export of C9ORF72 transcripts retaining expanded hexanucleotide repeats and reveal a novel promising therapeutic target for neuroprotection

Superoxide Dismutase (SOD)-mimetic M40403 is protective in cell and fly models of paraquat toxicity: Implications for Parkinson disease

Parkinson disease is a debilitating and incurable neurodegenerative disorder affecting 3c1-2% of people over 65 years of age. Oxidative damage is considered to play a central role in the progression of Parkinson disease and strong evidence links chronic exposure to the pesticide paraquat with the incidence of the disease, most probably through the generation of oxidative damage. In this work, we demonstrated in human SH-SY5Y neuroblastoma cells the beneficial role of superoxide dismutase (SOD) enzymes against paraquat-induced toxicity, as well as the therapeutic potential of the SOD-mimetic compound M40403. Having verified the beneficial effects of superoxide dismutation in cells, we then evaluated the effects using Drosophila melanogaster as an in vivo model. Besides protecting against the oxidative damage induced by paraquat treatment, our data demonstrated that in Drosophila M40403 was able to compensate for the loss of endogenous SOD enzymes, acting both at a cytosolic and mitochondrial level. Because previous clinical trials have indicated that the M40403 molecule is well tolerated in humans, this study may have important implication for the treatment of Parkinson disease

Basal mitophagy is widespread in <i>Drosophila</i> but minimally affected by loss of Pink1 or parkin.

The Parkinson's disease factors PINK1 and parkin are strongly implicated in stress-induced mitophagy in vitro, but little is known about their impact on basal mitophagy in vivo. We generated transgenic Drosophila melanogaster expressing fluorescent mitophagy reporters to evaluate the impact of Pink1/parkin mutations on basal mitophagy under physiological conditions. We find that mitophagy is readily detectable and abundant in many tissues, including Parkinson's disease-relevant dopaminergic neurons. However, we did not detect mitolysosomes in flight muscle. Surprisingly, in Pink1 or parkin null flies, we did not observe any substantial impact on basal mitophagy. Because these flies exhibit locomotor defects and dopaminergic neuron loss, our findings raise questions about current assumptions of the pathogenic mechanism associated with the PINK1/parkin pathway. Our findings provide evidence that Pink1 and parkin are not essential for bulk basal mitophagy in Drosophila They also emphasize that mechanisms underpinning basal mitophagy remain largely obscure

Innovative Medial Cushioning Orthoses Affect Peroneus Longus Electromyographic Activity during Running

Background: Over-supination processes of the foot and ankle involving peroneus longus (PL) damage during running sports have been treated conservatively with passive control tools, such as tapes, braces, or external ankle supports, but the effect of orthoses with typical lateral wedging orthoses (TLWO) on the muscular activity of PL during running remains unclear. Here we investigate the effects of innovative medial cushioning orthoses (IMCO) on PL activity during the full running gait cycle. In addition, we wished to ascertain the effects of innovative medial cushioning orthoses (IMCO) on PL activity during running. Methods: Thirty-one healthy recreational runners (mean age 34.5 ± 3.33) with neutral foot posture index scores, were selected to participate in the present study. They ran on a treadmill at 9 km/h wearing seven different orthoses (NRS, IMCO 3 mm, IMCO 6 mm, IMCO 9 mm, TLWO 3 mm, TLWO 6 mm and TLWO 9 mm), randomly performed on the same day while electromyographic activity of the PL muscle was recorded. Statistical intraclass correlation coefficient (ICC) to test reliability was carried out and the Wilcoxon test with Bonferroni’s correction was developed to analyze the differences between the conditions. Results: the reliability of all assessments showed data higher than 0.81, that is, “almost perfect reliability”; all EMG PL values wearing either TLWO or IMCO showed a statistically significant reduction versus NRS during the fully analyzed running gait cycle; the highest difference was set on NRS 23.08 ± 6.67 to TLWO 9 mm 17.77 ± 4.794 (p < 0.001). Conclusions: Muscular EMG activity of the PL during the full running gait cycle decreases when wearing either TLWO or IMCO relative to NRS; therefore, these orthoses could be prescribed to treat the strain and overload pathologies of PL. In addition, IMCO—as it less thick, compared with TLWO—can be used when aiming to achieve better running econom

Habitat differences filter functional diversity of low dispersive microscopic animals (Acari, Halacaridae)

We are starting to appreciate that microscopic animals are not as widespread as previously thought, but we still ignore to what extent and through which mechanisms the environment selects for specific communities or traits in microscopic animals. We here analyse the functional diversity of marine mite communities living in a seagrass meadow across two habitats: the leaves and the matte. The strictly benthic lifestyle and the conserved morphology of mites allow for unambiguous characterisation of their functional traits, while the discrete nature of the two habitats alleviates the uncertainty in their ecological characterisation. Our results show that habitat filters the distribution of certain traits favouring a higher diversity, dispersion, and evenness of functional traits in the matte than in the leaves. We further observed temporal variations in the functional diversity of communities, following the changes in biomass and structure of seagrass leaves. However, despite the stark differences between the two habitats, the filtering effect is partial and affects mostly relative species abundances. Our study emphasises the need of moving from a taxonomical towards a functional view of ecological studies of microscopic organisms. This integrative approach is key to achieve a mechanistic understanding of their habitat and distribution patterns.Peer reviewe

Modeling Pathogenic Mutations of Human Twinkle in Drosophila Suggests an Apoptosis Role in Response to Mitochondrial Defects

The human gene C10orf2 encodes the mitochondrial replicative DNA helicase Twinkle, mutations of which are responsible for a significant fraction of cases of autosomal dominant progressive external ophthalmoplegia (adPEO), a human mitochondrial disease caused by defects in intergenomic communication. We report the analysis of orthologous mutations in the Drosophila melanogaster mitochondrial DNA (mtDNA) helicase gene, d-mtDNA helicase. Increased expression of wild type d-mtDNA helicase using the UAS-GAL4 system leads to an increase in mtDNA copy number throughout adult life without any noteworthy phenotype, whereas overexpression of d-mtDNA helicase containing the K388A mutation in the helicase active site results in a severe depletion of mtDNA and a lethal phenotype. Overexpression of two d-mtDNA helicase variants equivalent to two human adPEO mutations shows differential effects. The A442P mutation exhibits a dominant negative effect similar to that of the active site mutant. In contrast, overexpression of d-mtDNA helicase containing the W441C mutation results in a slight decrease in mtDNA copy number during the third instar larval stage, and a moderate decrease in life span in the adult population. Overexpression of d-mtDNA helicase containing either the K388A or A442P mutations causes a mitochondrial oxidative phosphorylation (OXPHOS) defect that significantly reduces cell proliferation. The mitochondrial impairment caused by these mutations promotes apoptosis, arguing that mitochondria regulate programmed cell death in Drosophila. Our study of d-mtDNA helicase overexpression provides a tractable Drosophila model for understanding the cellular and molecular effects of human adPEO mutations

Superoxide dismutating molecules rescue the toxic effects of PINK1 and parkin loss.

Reactive oxygen species exert important functions in regulating several cellular signalling pathways. However, an excessive accumulation of reactive oxygen species can perturb the redox homeostasis leading to oxidative stress, a condition which has been associated to many neurodegenerative disorders. Accordingly, alterations in the redox state of cells and mitochondrial homeostasis are established hallmarks in both familial and sporadic Parkinson's disease cases. PINK1 and Parkin are two genes which account for a large fraction of autosomal recessive early-onset forms of Parkinson's disease and are now firmly associated to both mitochondria and redox homeostasis. In this study we explored the hypothesis that superoxide anions participate in the generation of the Parkin and PINK1 associated phenotypic effect by testing the capacity of endogenous and exogenous superoxide dismutating molecules to rescue the toxic effects induced by loss of PINK1 or Parkin, in both cellular and fly models. Our results demonstrate the positive effect of an increased level of superoxide dismutase proteins on the pathological phenotypes, both in vitro and in vivo. A more pronounced effectiveness for mitochondrial SOD2 activity points to the superoxide radicals generated in the mitochondrial matrix as the prime suspect in the definition of the observed phenotypes. Moreover, we also demonstrate the efficacy of a SOD-mimetic compound, M40403, to partially ameliorate PINK1/Parkin phenotypes in vitro and in vivo. These results support the further exploration of SOD-mimetic compounds as a therapeutic strategy against Parkinson's disease

A dataset of Tanaidacea from the Iberian Peninsula and surrounding areas

We describe a dataset on the crustacean Order Tanaidacea from the coasts of the Iberian Peninsula and surrounding seas, including the archipelagos of the Azores, Madeira, Savage, and the Canary Islands. The dataset gathers the records from all available sources published between 1828 to 2019, which were collected following a standardized Google Scholar search and cross checking each article’s reference lists. For each record, the dataset includes taxonomic, geographical, and ecological information, as well as remarks regarding the sampling methods. The dataset was further completed with 52 additional unpublished records obtained from screening the collections of the University Complutense of Madrid gathered from 35 shallow water surveys. Furthermore, 698 records from different oceanographic deep-sea campaigns have also been included. In total, 3456 records from 186 species in 22 families have been compiled. The dataset organises the current published and unpublished knowledge on tanaidaceans in the area and, by making it open access, it will allow comparisons of the distribution of tanaidaceans in zoogeographic studies.&nbsp

Propuesta en Supply Chain Management y logística en la empresa Fabrica de Licores del Tolima

Se presenta una recopilación del análisis de cada uno de los componentes importantes de la logística y la cadena de suministro de una empresa con el fin de poder realizar un diagnóstico de la situación actual de la compañía, ya que es a través de estos que se puede entregar al cliente productos de buena calidad y en el menor tiempo posible aumentando las ventas y poniendo en práctica todo lo aprendido.A compilation of the analysis of each of the important components of logistics and the supply chain of a company is presented in order to be able to make a diagnosis of the current situation of the company, since it is through these that it is possible to Deliver good quality products to the customer in the shortest time possible, increasing sales and putting everything learned into practice

Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration.

Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders