Neurodegeneration, cell signaling and neuroreparative strategies

Funding Information: This work was partly supported by the grant UID/DTP/04138/2019-21 (iMed.ULisboa) as well as La Caixa Foundation and -Luzón Foundation through project HR21-00931. VP acknowledges financial support from the Spanish Ministry of Science through the Ramón y Cajal grant RYC2019-027489-I.publishersversionpublishe

Neurodegeneration, cell signaling and neuroreparative strategies, Volume II

Funding Information: This work was partly supported by the grant UID/DTP/04138/2019-22 (iMed.ULisboa) as well as La Caixa Foundation and Francisco Luzón Foundation through project HR21-00931. VP acknowledges financial support from the Spanish Ministry of Science through the Ramón y Cajal grant RYC2019-027489-I.publishersversionpublishe

Heterocyclic GSK-3 allosteric modulators

[ES] La presente invención se refiere a derivados heterocíclicos de quinolinas sustituidas como inhibidores alostéricos del enzima glucógeno sintasa quinasa 3 (GSK-3). Estos compuestos, por tanto, son útiles para la fabricación de un medicamento para el tratamiento y/o prevención de enfermedades en las que GSK-3 esté implicada, tales como, enfermedades neurodegenerativas, enfermedades inflamatorias, cáncer, diabetes, así como para promover diversos procesos regenerativos.[EN] The invention relates to heterocyclic derivatives of substituted quinolines as allosteric inhibitors of the glycogen synthase kinase 3 (GSK-3) enzyme. Thus, said compounds can be used in the production of a drug for the treatment and/or prevention of diseases in which GSK-3 is involved, such as: neurodegenerative diseases, inflammatory diseases, cancer and diabetes, as well as to promote a plurality of regenerative processes.Peer reviewedConsejo Superior de Investigaciones Científicas (España)A1 Solicitud de patente con informe sobre el estado de la técnic

Estudio del potencial de bioconjugados Quantum Dots para el marcaje específico de dianas involucradas en Esclerosis Lateral Amiotrófica

La investigación biomédica se encuentra en continuo avance y requiere la implantación de técnicas novedosas y prometedoras que permitan esclarecer mecanismos de enfermedades y seleccionar medicamentos eficaces para las mismas. El fin de estas técnicas es poder aplicar un tratamiento individualizado a cada paciente, es decir, implantar la medicina personalizada y para ello son necesarios biomarcadores y sensores efectivos. La técnica Multicolor Multicycle Molecular profiling (M3P), la cual se quiere aplicar en patologías de gran complejidad molecular como la esclerosis lateral amiotrofia (ELA), entre otras, utiliza Quantum Dots (QDs), nanopartículas con características fotoluminiscentes únicas y ventajosas sobre los fluoróforos tradicionales y con gran potencial como herramienta puntera en el campo de la biomedicina. En este trabajo se muestran los resultados obtenidos tras la realización de distintos inmunoensayos de QDs para estudiar su efectividad de marcaje de proteínas, la penetrabilidad en el núcleo y en consecuencia su potencial para seleccionar fármacos eficaces para patologías complejas como la EL

Small molecules targeting glycogen synthase kinase 3 as potential drug candidates for the treatment of retinitis pigmentosa

6 p.-5 fig.Retinitis pigmentosa (RP) is an inherited retinal dystrophy that courses with progressive degeneration of retinal tissue and loss of vision. Currently, RP is an unpreventable, incurable condition. We propose glycogen synthase kinase 3 (GSK-3) inhibitors as potential leads for retinal cell neuroprotection, since the retina is also a part of the central nervous system and GSK-3 inhibitors are potent neuroprotectant agents. Using a chemical genetic approach, diverse small molecules with different potency and binding mode to GSK-3 have been used to validate and confirm GSK-3 as a pharmacological target for RP. Moreover, this medicinal chemistry approach has provided new leads for the future disease-modifying treatment of RP.This work has been partially funded by the Spanish MINECO grants (SAF2012-37979-C03-01 to AM and SAF2013-41059-R to EJdlR).Peer reviewe

Sensitivity of hematopoietic stem cells to mitochondrial dysfunction by SdhD gene deletion

It is established that hematopoietic stem cells (HSC) in the hypoxic bone marrow have adapted their metabolism to oxygen-limiting conditions. This adaptation includes suppression of mitochondrial activity, induction of anerobic glycolysis, and activation of hypoxia-inducible transcription factor 1α (Hif1α)-dependent gene expression. During progression of hematopoiesis, a metabolic switch towards mitochondrial oxidative phosphorylation is observed, making this organelle essential for determining cell fate choice in bone marrow. However, given that HSC metabolism is essentially oxygen-independent, it is still unclear whether functional mitochondria are absolutely required for their survival. To assess the actual dependency of these undifferentiated cells on mitochondrial function, we have performed an analysis of the hematopoiesis in a mouse mutant, named SDHD-ESR, with inducible deletion of the mitochondrial protein-encoding SdhD gene. This gene encodes one of the subunits of the mitochondrial complex II (MCII). In this study, we demonstrate that, in contrast to what has been previously established, survival of HSC, and also myeloid and B-lymphoid progenitors, depends on proper mitochondrial activity. In addition, gene expression analysis of these hematopoietic lineages in SDHD-ESR mutants calls into question the proposed activation of Hif1α in response to MCII dysfunction.Ministerio de Ciencia e Innovación SAF2009-06970Junta de Andalucía CTS-4589Instituto de Salud Carlos III PI-0355-201

TTBK1 and CK1 inhibitors restore TDP-43 pathology and avoid disease propagation in lymphoblast from Alzheimer’s disease patients

IntroductionTDP-43 proteinopathy in Alzheimer’s disease (AD) patients is recently emerging as a relevant pathomolecular event that may have been overlooked. Recent results in immortalized lymphocytes from AD patients have shown not only an increase of post-translational modifications in TDP-43, such as hyperphosphorylation and fragmentation, but also its prionic behaviour and cell-to-cell disease transmission. With the main goal to advance therapeutic interventions, we present in this work different kinase inhibitors with potential to restore this pathological mechanism.MethodologyWe have used immortalized lymphocytes from healthy controls and AD severe patients to evaluate the correction of TDP-43 pathology after the treatment with previously synthetized TTBK1 and CK1 inhibitors. Moreover we used the conditioned mediums of these cells to perform different disease propagation experiments.ResultsTDP-43 pathology observed in lymphoblasts from severe AD patients is reduced after the treatment with TTBK1 and CK1 inhibitors (decreasing phosphorylation and increasing nuclear localisation), Furthermore, the significant increase in TDP-43 phosphorylation, cytoplasmic accumulation and aberrant F-actin protrusions (TNT-like structures) observed in control cells growing in CM from AD lymphoblasts were abolished when the CM from AD lymphoblasts treated with previously reported TTBK1 and CK1 inhibitors were used. In addition, the cytosolic transport mediated by molecular motors of the receptor cells was altered with the induced TDP-43 pathology, but it was not produced with the abovementioned pretreated CMs.ConclusionTTBK1 and CK1 inhibitors, specially VNG1.47 and IGS2.7 compounds, restore TDP-43 pathology and avoid cell-to-cell propagation in immortalized lymphocytes from AD patients, being excellent candidates for the future therapy of this prevalent and devastating disease