The Huntington's disease mutation impairs Huntingtin's role in the transport of NF-κB from the synapse to the nucleus

Expansion of a polyglutamine (polyQ) tract in the Huntingtin (Htt) protein causes Huntington's disease (HD), a fatal inherited neurodegenerative disorder. Loss of the normal function of Htt is thought to be an important pathogenetic component of HD. However, the function of wild-type Htt is not well defined. Htt is thought to be a multifunctional protein that plays distinct roles in several biological processes, including synaptic transmission, intracellular transport and neuronal transcription. Here, we show with biochemical and live cell imaging studies that wild-type Htt stimulates the transport of nuclear factor κ light-chain-enhancer of activated B cells (NF-κB) out of dendritic spines (where NF-κB is activated by excitatory synaptic input) and supports a high level of active NF-κB in neuronal nuclei (where NF-κB stimulates the transcription of target genes). We show that this novel function of Htt is impaired by the polyQ expansion and thus may contribute to the etiology of HD

Involvement of P2X and P2Y receptors in microglial activation in vivo

Microglial cells are the primary immune effector cells in the brain. Extracellular ATP, e.g., released after brain injury, may initiate microglial activation via stimulation of purinergic receptors. In the rat nucleus accumbens (NAc), the involvement of P2X and P2Y receptors in the generation of microglial reaction in vivo was investigated. A stab wound in the NAc increased immunoreactivity (IR) for P2X1,2,4,7 and P2Y1,2,4,6,12 receptors on microglial cells when visualized with confocal laser scanning microscopy. A prominent immunolabeling of P2X7 receptors with antibodies directed against the ecto- or endodomain was found on Griffonia simplicifolia isolectin-B4-positive cells. Additionally, the P2X7 receptor was colocalized with active caspase 3 but not with the anti-apoptotic marker pAkt. Four days after local application of the agonists α,βmeATP, ADPβS, 2MeSATP, and BzATP, an increase in OX 42- and G. simplicifolia isolectin-IR was observed around the stab wound, quantified both densitometrically and by counting the number of ramified and activated microglial cells, whereas UTPγS appeared to be ineffective. The P2 receptor antagonists PPADS and BBG decreased the injury-induced increase of these IRs when given alone and in addition inhibited the agonist effects. Further, the intra-accumbally applied P2X7 receptor agonist BzATP induced an increase in the number of caspase-3-positive cells. These results indicate that ATP, acting via different P2X and P2Y receptors, is a signaling molecule in microglial cell activation after injury in vivo. The up-regulation of P2X7-IR after injury suggests that this receptor is involved in apoptotic rather than proliferative effects

Structural Properties of Polyglutamine Aggregates Investigated via Molecular Dynamics Simulations

Polyglutamine (polyQ) beta-stranded aggregates constitute the hallmark of Huntington disease. The disease is fully penetrant when Q residues are more than 36-40 ("disease threshold"). Here, based on a molecular dynamics study on polyQ helical structures of different shapes and oligomeric states, we suggest that the stability of the aggregates increases with the number of monomers, while it is rather insensitive to the number of Qs in each monomer. However, the stability of the single monomer does depend on the number of side-chain intramolecular H-bonds, and therefore oil the number of Qs. If such number is lower than that of the disease threshold, the beta-stranded monomers are unstable and hence may aggregate with lower probability, consistently with experimental findings. Our results provide a possible interpretation of the apparent polyQ length dependent-toxicity, and they do not support the so-called "structural threshold hypothesis", which supposes a transition from random coil to a beta-sheet structure only above the disease threshold

Neuronal Deletion of Caspase 8 Protects against Brain Injury in Mouse Models of Controlled Cortical Impact and Kainic Acid-Induced Excitotoxicity

system. mice demonstrated superior survival, reduced seizure severity, less apoptosis, and reduced caspase 3 processing. Uninjured aged knockout mice showed improved learning and memory, implicating a possible role for caspase 8 in cognitive decline with aging.Neuron-specific deletion of caspase 8 reduces brain damage and improves post-traumatic functional outcomes, suggesting an important role for this caspase in pathophysiology of acute brain trauma

The modular systems biology approach to investigate the control of apoptosis in Alzheimer's disease neurodegeneration

Apoptosis is a programmed cell death that plays a critical role during the development of the nervous system and in many chronic neurodegenerative diseases, including Alzheimer's disease (AD). This pathology, characterized by a progressive degeneration of cholinergic function resulting in a remarkable cognitive decline, is the most common form of dementia with high social and economic impact. Current therapies of AD are only symptomatic, therefore the need to elucidate the mechanisms underlying the onset and progression of the disease is surely needed in order to develop effective pharmacological therapies. Because of its pivotal role in neuronal cell death, apoptosis has been considered one of the most appealing therapeutic targets, however, due to the complexity of the molecular mechanisms involving the various triggering events and the many signaling cascades leading to cell death, a comprehensive understanding of this process is still lacking. Modular systems biology is a very effective strategy in organizing information about complex biological processes and deriving modular and mathematical models that greatly simplify the identification of key steps of a given process. This review aims at describing the main steps underlying the strategy of modular systems biology and briefly summarizes how this approach has been successfully applied for cell cycle studies. Moreover, after giving an overview of the many molecular mechanisms underlying apoptosis in AD, we present both a modular and a molecular model of neuronal apoptosis that suggest new insights on neuroprotection for this disease

Angiogenic and antifibrotic properties of progenitor cells from the vascular stromal fraction of adipose tissue in systemic scleroderma

La Sclérodermie Systémique (ScS) est une maladie auto-immune rare caractérisée par une vasculopathie ischémique et des lésions de fibrose touchant la peau et les organes profonds. Les thérapeutiques conventionnelles sont limitées, justifiant la recherche de nouvelles stratégies. Notre équipe est pionnière dans le développement de la Fraction Vasculaire Stromale (FVS) du tissu adipeux autologue, concentré de cellules régénératives non adipocytaires, pour la prise en charge du handicap des mains et du visage de ces patients. Les résultats mitigés des essais cliniques imposent de mieux comprendre les propriétés biologiques sous-tendant l’efficacité thérapeutique de la FVS dans un contexte de ScS. L’objectif de ce travail est de rechercher un éventuel impact du contexte autologue de la ScS sur le potentiel angiogénique et antifibrotique de la FVS et des progéniteurs mésenchymateux du tissu adipeux. Nous montrons que le potentiel angiogénique de la FVS extraite chez des patients sclérodermiques est maintenu, bien que légèrement réduit, et ce malgré la mise en évidence d’une signature transcriptomique différentielle. De plus, la FVS de donneurs sains permet de réduire l’expression de marqueurs de fibrose in vitro. Par ailleurs, les propriétés paracrines de la composante mésenchymateuse de la FVS de patients sclérodermiques sont similaires à celles de donneurs sains.Au total, les résultats supportent le développement d’approches autologues dérivées du tissu adipeux dans la ScS. Ce travail ouvre des perspectives d’ingénierie cellulaire ou moléculaire dans le but de renforcer l’efficacité thérapeutique de ces produits de thérapie cellulaire.Systemic scleroderma (SSc) is a rare autoimmune disease characterized by an ischemic vasculopathy and fibrosis of cutaneous tissue and visceral organs. Conventional therapies are limited, justifying the search for new strategies. Our team is a pioneer in the development of Stromal Vascular Fraction (SVF) from autologous adipose tissue, a concentrate of non-adipose regenerative cells, for the management of hand and facial disability in these patients. The mixed results of clinical trials require a better understanding of the biological properties underlying the therapeutic efficacy of SVF in the context of SSc. The objective of this work is to investigate a possible impact of the autologous context of SSc on the angiogenic and antifibrotic potential of SVF and adipose-derived mesenchymal stem cells. We show that the angiogenic potential of SVF extracted from patients with SSc is maintained, albeit slightly reduced, despite the identification of a differential transcriptomic signature. Moreover, SVF from healthy donors induces a reduction in the expression of fibrosis markers in vitro. Furthermore, the paracrine properties of the mesenchymal component of SVF from patients suffering from SSc are similar to those from healthy donors.Overall, the results support the development of autologous approaches derived from adipose tissue in SSc. This work opens perspectives of cell or molecular engineering approaches in order to enhance the therapeutic efficacy of these cell therapy products

Thérapies cellulaires appliquées à la sclérodermie systémique : état des lieux & perspectives

La Sclérodermie Sytémique (ScS) est une maladie auto-immune rare et complexe qui touche environ 10 000 personnes en France. Les thérapeutiques conventionnelles reposent sur la combinaison de traitements immunomodulateurs et symptomatiques mais se révèlent souvent insuffisantes, notamment pour les patients souffrant de formes sévères et rapidement évolutives. Dans ce contexte, poursuivre la recherche d'options thérapeutiques pour les patients atteints de ScS est essentiel et les approches de thérapies cellulaires constituent un véritable espoir. À ce jour, seule l’autogreffe de cellules souches hématopoïétiques, responsable d’un reset immunologique et de la production d’un système immunitaire plus tolérant, a permis une réduction significative de la morbi-mortalité. Mais cette intensification thérapeutique avec greffe de cellules souches hématopoïétiques n’est proposée que dans les formes sévères de sclérodermie systémique après validation de l’indication par un comité d’experts. Le développement d’approches systémiques utilisant les cellules souches mésenchymateuses (CSM) se justifie aisément dans la ScS de par leurs propriétés immunomodulatrice, pro-angiogénique et trophique. Bien que les résultats préliminaires de ces travaux soient encourageants, le devenir au long cours de cellules allogéniques chez un patient souffrant d’un trouble de l’immunité tel que la ScS pourrait en freiner le développement. Par ailleurs, des approches de thérapies cellulaires autologues dérivées du tissu adipeux à visée locale telles que la fraction vasculaire stromale et les CSM sont actuellement à l’étude dans la prise en charge du handicap du visage et des mains associées à la ScS

Adipose-Derived Stem Cells from Systemic Sclerosis Patients Maintain Pro-Angiogenic and Antifibrotic Paracrine Effects In Vitro

Innovative therapies based on autologous adipose-derived stem/stromal cells (ASC) are currently being evaluated for treatment of systemic sclerosis (SSc). Although paracrine angiogenic and antifibrotic effects are considered the predominant mechanisms of ASC therapeutic potential, the impact of SSc on ASC paracrine functions remains controversial. In this study, phenotype, senescence, differentiation potential, and molecular profile were determined in ASC from SSc patients (SSc-ASC) (n = 7) and healthy donors (HD-ASC) (n = 7). ASC were co-cultured in indirect models with dermal fibroblasts (DF) from SSc patients or endothelial cells to assess their pro-angiogenic and antifibrotic paracrine effects. The angiogenic activity of endothelial cells was measured in vitro using tube formation and spheroid assays. DF collagen and alpha smooth muscle actin (αSMA) content were quantified after five days of co-culture with ASC. Differentiation capacity, senescence, and mRNA profiles did not differ significantly between SSc-ASC and HD-ASC. SSc-ASC retained the ability to stimulate angiogenesis through paracrine mechanisms; however, functional assays revealed reduced potential compared to HD-ASC. DF fibrosis markers were significantly decreased after co-culture with SSc-ASC. Together, these results indicate that SSc effects do not significantly compromise the angiogenic and the antifibrotic paracrine properties of ASC, thereby supporting further development of ASC-based autologous therapies for SSc treatment

Médicament et alicament anti-cholestérol (concurrence ou complémentarité ?)

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF