Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy.

BackgroundThe trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. There is critical knowledge gap in understanding how tau is released and transmitted, and how that is dysregulated in diseases. Previously, we reported that lysine acetyltransferase p300/CBP acetylates tau and regulates its degradation and toxicity. However, whether p300/CBP is involved in regulation of tau secretion and propagation is unknown.MethodWe investigated the relationship between p300/CBP activity, the autophagy-lysosomal pathway (ALP) and tau secretion in mouse models of tauopathy and in cultured rodent and human neurons. Through a high-through-put compound screen, we identified a new p300 inhibitor that promotes autophagic flux and reduces tau secretion. Using fibril-induced tau spreading models in vitro and in vivo, we examined how p300/CBP regulates tau propagation.ResultsIncreased p300/CBP activity was associated with aberrant accumulation of ALP markers in a tau transgenic mouse model. p300/CBP hyperactivation blocked autophagic flux and increased tau secretion in neurons. Conversely, inhibiting p300/CBP promoted autophagic flux, reduced tau secretion, and reduced tau propagation in fibril-induced tau spreading models in vitro and in vivo.ConclusionsWe report that p300/CBP, a lysine acetyltransferase aberrantly activated in tauopathies, causes impairment in ALP, leading to excess tau secretion. This effect, together with increased intracellular tau accumulation, contributes to enhanced spreading of tau. Our findings suggest that inhibition of p300/CBP as a novel approach to correct ALP dysfunction and block disease progression in tauopathy

Content validity of a scale to measure parental mediation in the use of technologies in adolescents

La mediación parental es un elemento importante en la formación de la ciudadanía digital en los adolescentes. El presente estudio se propuso analizar la validez de contenido de una escala para medir la mediación parental en el uso de las tecnologías por adolescentes. Se utilizó el juicio de expertos aplicando el método de agregados individuales. Participaron en el estudio siete jueces con experiencia en la investigación acerca de la mediación parental o la ciudadanía digital. Los resultados del coeficiente de validez de contenido sugieren la no inclusión de cuatro ítems en la escala. La nueva versión se conformó con 25 ítems con adecuada validez de contenido. Se concluyó que la escala cuenta con evidencias de validez de contenido suficientes para ser utilizada en la medición del constructo en adolescentes mexicanosParental mediation is an important element in the adolescent’s digital citizenship formation. The present study aimed to analyze the content validity of a parental mediation scale in the technologies use by adolescents. Expert judgment was used applying the individual aggregation method. Seven judges with experience in research about parental mediation or digital citizenship participated in the study. The results of the content validity coefficient suggest the non-inclusion of four items in the scale. The new version was conformed of 26 items with adequate content validity. It was concluded that the scale has sufficient evidence of content validity to be used in the measurement of the construct in Mexican adolescent

Una medida del riesgo de reincidencia en menores infractores

Tretzenes Jornades de Foment de la Investigació de la FCHS (Any 2007-2008

Gαq activation modulates autophagy by promoting mTORC1 signaling.

The mTORC1 node plays a major role in autophagy modulation. We report a role of the ubiquitous Gαq subunit, a known transducer of plasma membrane G protein-coupled receptors signaling, as a core modulator of mTORC1 and autophagy. Cells lacking Gαq/11 display higher basal autophagy, enhanced autophagy induction upon different types of nutrient stress along with a decreased mTORC1 activation status. They are also unable to reactivate mTORC1 and thus inactivate ongoing autophagy upon nutrient recovery. Conversely, stimulation of Gαq/11 promotes sustained mTORC1 pathway activation and reversion of autophagy promoted by serum or amino acids removal. Gαq is present in autophagic compartments and lysosomes and is part of the mTORC1 multi-molecular complex, contributing to its assembly and activation via its nutrient status-sensitive interaction with p62, which displays features of a Gαq effector. Gαq emerges as a central regulator of the autophagy machinery required to maintain cellular homeostasis upon nutrient fluctuations.We thank Paula Ramos, Susana Rojo-Berciano, and Laura López for helpful technicalassistance. Dr. Marta Cruces (Universidad Autónoma de Madrid, Spain) for herinvaluable help regarding the liver explants experiments, Dr. Badford Berk (University ofRochester, NY, USA) for providing the GFP-Flag-PB1-p62 plasmid, Drs. Stefan Offer-manns and Nina Wettschureck (Max-Planck-Institute for Heart and Lung Research,Germany) for providing Tie2-CreERT2; Gnaq f/f; Gna11−/−[EC-q/11-KO) mice, andDr. Guzmán Sánchez for scientific advice. We thank also Ricardo Ramos from theGenomic facility of Fundación Parque Científico de Madrid (Universidad Autónoma deMadrid, Spain) and Gemma Rodríguez-Tarduchy from the Genomic facility of theInstituto de Investigaciones Biomédicas“Alberto Sols”for their help with cell linesauthentication. The help from CBMSO Animal Care, Flow Cytometry, Electron andOptical and Confocal Microscopy facilities is also acknowledged. This work was sup-ported by Ministerio de Economía; Industria y Competitividad (MINECO) of Spain(grant SAF2017-84125-R to F.M.), (grant BFU2017-83379-R to A.M.A.), Instituto deSalud Carlos III (PI18/01662 to CR, co-funded with European FEDER contribution),CIBERCV-Instituto de Salud Carlos III, Spain (grant CB16/11/00278 to F.M., co-fundedwith European FEDER contribution), Fundación Ramón Areces (to C.R. and F.M.) andPrograma de Actividades en Biomedicina de la Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE to F.M. and NIH grants AG021904 and AG038072 to A.M.C. Wealso acknowledge the support of a Contrato para la Formación del Profesorado Uni-versitario (FPU13/04341) and (FPU14/06670), an EMBO short-term fellowship (ASTF600-2016). We also acknowledge institutional support to the CBMSO from FundaciónRamón Areces.S

IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome

Expansion of the polyglutamine repeat within the protein Huntingtin (Htt) causes Huntington's disease, a neurodegenerative disease associated with aging and the accumulation of mutant Htt in diseased neurons. Understanding the mechanisms that influence Htt cellular degradation may target treatments designed to activate mutant Htt clearance pathways. We find that Htt is phosphorylated by the inflammatory kinase IKK, enhancing its normal clearance by the proteasome and lysosome. Phosphorylation of Htt regulates additional post-translational modifications, including Htt ubiquitination, SUMOylation, and acetylation, and increases Htt nuclear localization, cleavage, and clearance mediated by lysosomal-associated membrane protein 2A and Hsc70. We propose that IKK activates mutant Htt clearance until an age-related loss of proteasome/lysosome function promotes accumulation of toxic post-translationally modified mutant Htt. Thus, IKK activation may modulate mutant Htt neurotoxicity depending on the cell's ability to degrade the modified species

New and noteworthy bird records from the east slope of the andes of colombia

We present significant new information on the distribution and status of 138 speciesof birds from the Andean East Slope of Colombia, based upon fieldwork between1990 and 2000 at 28 sites from central Dpto. Boyacá south to the Ecuador border.The first Colombian specimens of two species (Campylopterus villaviscensio, NapoSabrewing; Myrmotherula spodionota, Foothill Antwren) are reported. Three othertaxa (Ocreatus underwoodii addae, Piculus leucolaemus leucolaemus andMyiophobus p. phoenicomitra), the first two sometimes considered species distinctfrom known Colombian forms, represent first reports from Colombia based uponsightings or photographs; we add several more sightings of two species (Pipreolachlorolepidota, Iridisornis analis) previously known from single sight records. Inall, we report 35 species from the Andean East Slope of Colombia for the first time,southward range extensions on this slope for 47 species, northward extensions for21, upward or downward altitudinal extensions for 19, filling in of major discontinuitiesin distribution for 22; for ten of the latter, known from very few reports, new informationindicates a continuous distribution and far greater abundance than previouslysupposed. Range extensions and previously undiscovered populations of severalrestricted-range, Vulnerable, Near-threatened and Threatened species help toemphasize the importance of implementing conservation measures in the face of the increasing colonization pressures and insecurity. Based on our observations, wepresent several recommendations for setting conservation priorities in this rich butstill relatively poorly known region

Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease

Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before β-amyloid (Aβ) deposits extracellularly in the presenilin (PS) 1/Aβ precursor protein (APP) mouse model of β-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Aβ. Purified AVs contain APP and β-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent γ-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Aβ production. Our results, therefore, link β-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD

Autophagy fights disease through cellular self-digestion

Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62766/1/nature06639.pd

Dative constructions in Romance and beyond

This book offers a comprehensive account of dative structures across languages –with an important, though not exclusive, focus on the Romance family. As is well-known, datives play a central role in a variety of structures, ranging from ditransitive constructions to cliticization of indirect objects and differentially marked direct objects, and including also psychological predicates, possessor or causative constructions, among many others. As interest in all these topics has increased significantly over the past three decades, this volume provides an overdue update on the state of the art. Accordingly, the chapters in this volume account for both widely discussed patterns of dative constructions as well as those that are relatively unknown