Heat Shock Proteins Regulatory Role in Neurodevelopment

Heat shock proteins (Hsps) are a large family of molecular chaperones that are well-known for their roles in protein maturation, re-folding and degradation. While some Hsps are constitutively expressed in certain regions, others are rapidly upregulated in the presence of stressful stimuli. Numerous stressors, including hyperthermia and hypoxia, can induce the expression of Hsps, which, in turn, interact with client proteins and co-chaperones to regulate cell growth and survival. Such interactions must be tightly regulated, especially at critical points during embryonic and postnatal development. Hsps exhibit specific patterns of expression consistent with a spatio-temporally regulated role in neurodevelopment. There is also growing evidence that Hsps may promote or inhibit neurodevelopment through specific pathways regulating cell differentiation, neurite outgrowth, cell migration, or angiogenesis. This review will examine the regulatory role that these individual chaperones may play in neurodevelopment, and will focus specifically on the signaling pathways involved in the maturation of neuronal and glial cells as well as the underlying vascular network

A theory of network alteration for the Mullins effect

International audienceThis paper reports on the development of a new network alteration theory to describe the Mullins effect. The stress-softening phenomenon that occurs in rubber-like materials during cyclic loading is analysed from a physical point of view. The Mullins effect is considered to be a consequence of the breakage of links inside the material. Both filler-matrix and chain interaction links are involved in the phenomenon. This new alteration theory is implemented by modifying the eight-chains constitutive equation of Arruda and Boyce (J. Mech. Phys. Solids 41 (2) (1993) 389). In the present method the parameters of the eight-chains model, denoted C-R and N in the bibliography, become functions of the maximum chain stretch ratio. The accuracy of the resulting constitutive equation is demonstrated on cyclic uniaxial experiments for both natural rubbers and synthetic elastomers

Ventromedial medulla inhibitory neuron inactivation induces REM sleep without atonia and REM sleep behavior disorder

Despite decades of research, there is a persistent debate regarding the localization of GABA/glycine neurons responsible for hyperpolarizing somatic motoneurons during paradoxical (or REM) sleep (PS), resulting in the loss of muscle tone during this sleep state. Combining complementary neuroanatomical approaches in rats, we first show that these inhibitory neurons are localized within the ventromedial medulla (vmM) rather than within the spinal cord. We then demonstrate their functional role in PS expression through local injections of adeno-associated virus carrying specific short-hairpin RNA in order to chronically impair inhibitory neurotransmission from vmM. After such selective genetic inactivation, rats display PS without atonia associated with abnormal and violent motor activity, concomitant with a small reduction of daily PS quantity. These symptoms closely mimic human REM sleep behavior disorder (RBD), a prodromal parasomnia of synucleinopathies. Our findings demonstrate the crucial role of GABA/glycine inhibitory vmM neurons in muscle atonia during PS and highlight a candidate brain region that can be susceptible to α-synuclein-dependent degeneration in RBD patients

A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep

BACKGROUND: Peptidergic neurons containing the melanin-concentrating hormone (MCH) and the hypocretins (or orexins) are intermingled in the zona incerta, perifornical nucleus and lateral hypothalamic area. Both types of neurons have been implicated in the integrated regulation of energy homeostasis and body weight. Hypocretin neurons have also been involved in sleep-wake regulation and narcolepsy. We therefore sought to determine whether hypocretin and MCH neurons express Fos in association with enhanced paradoxical sleep (PS or REM sleep) during the rebound following PS deprivation. Next, we compared the effect of MCH and NaCl intracerebroventricular (ICV) administrations on sleep stage quantities to further determine whether MCH neurons play an active role in PS regulation. RESULTS: Here we show that the MCH but not the hypocretin neurons are strongly active during PS, evidenced through combined hypocretin, MCH, and Fos immunostainings in three groups of rats (PS Control, PS Deprived and PS Recovery rats). Further, we show that ICV administration of MCH induces a dose-dependant increase in PS (up to 200%) and slow wave sleep (up to 70%) quantities. CONCLUSION: These results indicate that MCH is a powerful hypnogenic factor. MCH neurons might play a key role in the state of PS via their widespread projections in the central nervous system

Differential Roles of Hyperglycemia and Hypoinsulinemia in Diabetes Induced Retinal Cell Death: Evidence for Retinal Insulin Resistance

Diabetes pathology derives from the combination of hyperglycemia and hypoinsulinemia or insulin resistance leading to diabetic complications including diabetic neuropathy, nephropathy and retinopathy. Diabetic retinopathy is characterized by numerous retinal defects affecting the vasculature and the neuro-retina, but the relative contributions of the loss of retinal insulin signaling and hyperglycemia have never been directly compared. In this study we tested the hypothesis that increased retinal insulin signaling and glycemic normalization would exert differential effects on retinal cell survival and retinal physiology during diabetes. We have demonstrated in this study that both subconjunctival insulin administration and systemic glycemic reduction using the sodium-glucose linked transporter inhibitor phloridzin affected the regulation of retinal cell survival in diabetic rats. Both treatments partially restored the retinal insulin signaling without increasing plasma insulin levels. Retinal transcriptomic and histological analysis also clearly demonstrated that local administration of insulin and systemic glycemia normalization use different pathways to counteract the effects of diabetes on the retina. While local insulin primarily affected inflammation-associated pathways, systemic glycemic control affected pathways involved in the regulation of cell signaling and metabolism. These results suggest that hyperglycemia induces resistance to growth factor action in the retina and clearly demonstrate that both restoration of glycemic control and retinal insulin signaling can act through different pathways to both normalize diabetes-induced retinal abnormality and prevent vision loss

Evidence for Paracrine Protective Role of Exogenous αA-Crystallin in Retinal Ganglion Cells

Expression and secretion of neurotrophic factors have long been known as a key mechanism of neuroglial interaction in the central nervous system. In addition, several other intrinsic neuroprotective pathways have been described, including those involving small heat shock proteins such as α-crystallins. While initially considered as a purely intracellular mechanism, both αA-crystallins and αB-crystallins have been recently reported to be secreted by glial cells. While an anti-apoptotic effect of such secreted αA-crystallin has been suggested, its regulation and protective potential remain unclear. We recently identified residue threonine 148 (T148) and its phosphorylation as a critical regulator of αA-crystallin intrinsic neuroprotective function. In the current study, we explored how mutation of this residue affected αA-crystallin chaperone function, secretion, and paracrine protective function using primary glial and neuronal cells. After demonstrating the paracrine protective effect of αA-crystallins secreted by primary Müller glial cells (MGCs), we purified and characterized recombinant αA-crystallin proteins mutated on the T148 regulatory residue. Characterization of the biochemical properties of these mutants revealed an increased chaperone activity of the phosphomimetic T148D mutant. Consistent with this observation, we also show that exogeneous supplementation of the phosphomimetic T148D mutant protein protected primary retinal neurons from metabolic stress despite similar cellular uptake. In contrast, the nonphosphorylatable mutant was completely ineffective. Altogether, our study demonstrates the paracrine role of αA-crystallin in the central nervous system as well as the therapeutic potential of functionally enhanced αA-crystallin recombinant proteins to prevent metabolic-stress induced neurodegeneration

Dystrophin Dp71 functions in the eye,phenotypic impacts

Le premier phénotype à avoir été décrit chez les patients souffrant de la dystrophie musculaire de Duchenne (DMD) est la dégénérescence musculaire progressive liée à l'absence du produit long issu du gène DMD : la dystrophine. Les différents travaux menésThe first phenotype to be described among patients suffering from the Duchenne muscular dystrophy (DMD) is the progressive muscular degeneration related to the absence of the hole DMD gene product: the dystrophin. Various work undertaken thereafter led t

Rôle de la dystrophine Dp71 dans l'oeil : Impacts phénotypiques

Le premier phénotype à avoir été décrit chez les patients souffrant de la dystrophie musculaire de Duchenne (DMD) est la dégénérescence musculaire progressive liée à l’absence du produit long issu du gène DMD : la dystrophine. Les différents travaux menés par la suite ont conduit à la mise en évidence d’autres troubles chez ces patients, affectant notamment leurs performances cognitives de façon non progressive. Ces travaux ont également permis de montrer que ces affections étaient liées aux produits courts du gène DMD et tout particulièrement à la Dp71. La Dp71 est le produit du gène majoritairement exprimé dans de nombreux tissus parmi lesquels le système nerveux central y compris la rétine. La découverte au milieu des années 1990, que 80% des patients DMD présentent une perturbation de la neurotransmission rétinienne, nous a conduit à étudier le rôle des dystrophines, et en particulier la Dp71 dans la rétine, à l’aide d’une souris transgénique pour laquelle l’expression de cette protéine a été invalidée. Cette étude nous a permis de montrer que la Dp71 est uniquement exprimé par les principales cellules gliales de la rétine, les cellules gliales de Müller, où elle est seulement accompagnée par l’utrophine, le produit d’un gène homologue du gène DMD. Nous avons ensuite montré que la Dp71 est responsable de la localisation de deux protéines, le canal potassique Kir4.1 et le canal aqueux AQP4 qui sont essentielles à la régulation de l’homéostasie dans la rétine. De plus, l’absence de Dp71 entraîne une augmentation importante de la mort neuronale suite à un épisode ischémique, mettant en exergue l’intervention de la Dp71 dans la régulation de l’homéostasie rétinienne. Lors de l’étude clinique de la souris déficiente pour la Dp71, nous avons découvert un autre phénomène pathologique lié à l’absence de cette protéine : une cataracte congénitale progressive. Les dystrophines n’ayant jamais été étudiées dans le cristallin, nous avons caractérisé leur expression dans cette structure et montré que la Dp71 est également le produit du gène DMD majoritaire présent. Elle est principalement exprimée à la membrane des fibres secondaires du cristallin où elle colocalise avec le β-dystroglycane et le canal aqueux AQP0. Bien que des études complémentaires soient nécessaires, ces résultats indiquent qu’elle participe à un complexe macromoléculaire responsable de la conservation de l’intégrité de la membrane des fibres secondaires du cristallin. L’ensemble de ces travaux met en évidence le rôle de la Dp71 dans la vision, aussi bien dans un tissu nerveux, la rétine, que dans un tissu épithélial très spécifique : le cristallin. The first phenotype to be described among patients suffering from the Duchenne muscular dystrophy (DMD) is the progressive muscular degeneration related to the absence of the hole DMD gene product: the dystrophin. Various work undertaken thereafter led to the description of others troubles among these patients, affecting in particular their cognitive performances in a nonprogressive way. These works also made it possible to show that these affections were particularly related to the DMD gene short products and particularly Dp71. Dp71 is the mainly expressed product of this gene in many tissus among which the central nervous system including the retina. The discovery, in the middle of the 1990’s, that 80% of the DMD patients present a disturbance of the retinal neurotransmission led us to study the role of the dystrophins and in particular Dp71 in the retina using a transgenic mouse in which the expression of this protein was inactivated. This study enabled us to show that this DMD gene product is only expressed by the main glial cells of the retina, the Müller glial cells, where it is only accompanied by the utrophin, the product of an homologous gene of the dystrophin. We have also shown that Dp71 was responsible for the localization of two proteins essential for the homeostasis regulation of the retina: the potassic channel Kir4.1 and the aqueous channel AQP4. Moreover the absence of Dp71 induce a significant increase in neuronal death following an ischaemic event putting forward the intervention of Dp71 in the regulation of retinal homeostasis. At the time of the clinical study of the defective mouse for the Dp71, we discovered another pathological phenomenon dependent on the absence of this protein: the development of a progressive congenital cataract. Since dystrophins had never been studied in the crystalline lens, we first characterized their expression in this structure and showed that Dp71 is also there the main DMD gene product and that it is mainly expressed in the membrane of the crystalline lens secondary fibers where it colocalize with the β-dystroglycane and the aquaporin channel AQP0. Although complementary studies are necessary, this seems to indicate that it takes part in a macromolecular complex responsible for the conservation of the integrity of the membrane of secondary fibres of the crystalline lens. The whole of this work puts forward the role of Dp71 in the vision, as well in one part of the central nervous system, the retina, as in a very specific epithelial tissue, the crystalline lens

Ces neurones qui nous font dormir !

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