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    ABSTRACT: Amyotrophic Lateral Sclerosis (ALS) is a motor neuron degenerative disease characterized by a progressive, and ultimately fatal, muscle paralysis. The human VAMP-Associated Protein B (hVAPB) is the causative gene of ALS type 8. Previous studies have shown that a loss-of-function mechanism is responsible for VAPB-induced ALS. Recently, a novel mutation in hVAPB (V234I) has been identified but its pathogenic potential has not been assessed. We found that neuronal expression of the V234I mutant allele in Drosophila (DVAP-V260I) induces defects in synaptic structure and microtubule architecture that are opposite to those associated with DVAP mutants and transgenic expression of other ALS-linked alleles. Expression of DVAP-V260I also induces aggregate formation, reduced viability, wing postural defects, abnormal locomotion behavior, nuclear abnormalities, neurodegeneration and upregulation of the heat-shock-mediated stress response. Similar, albeit milder, phenotypes are associated with the overexpression of the wild-type protein. These data show that overexpressing the wild-type DVAP is sufficient to induce the disease and that DVAP-V260I is a pathogenic allele with increased wild-type activity. We propose that a combination of gain- and loss-of-function mechanisms is responsible for VAPB-induced ALS.
    Biology open. 12/2013;
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    ABSTRACT: Neurons are more vulnerable to oxidative stress than astrocytes, the reasons for which have yet to be fully elucidated. Understanding the cellular and molecular mechanisms which contribute to this enhanced vulnerability is key to efforts aimed at ameliorating neuronal health and resilience to oxidative stress, particularly in the context of neurodegenerative disease, which is characterized by progressive dysfunction and loss of neurons specifically, and in which oxidative stress is considered a central aetiological contributor. Biological factors which may influence neuronal susceptibility to oxidative stress, in normal and neurodegenerative contexts, are reviewed in the present article, with a focus on properties intrinsic to the neuronal cell type and on properties related to neuronal reliance on surrounding astrocytes.
    Biochemical Society Transactions 12/2013; 41(6):1541-1545.
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    ABSTRACT: Synaptobrevin II (sybII) is a key fusogenic molecule on synaptic vesicles (SVs) therefore the active maintenance of both its conformation and location in sufficient numbers on this organelle is critical in both mediating and sustaining neurotransmitter release. Recently three proteins have been identified having key roles in the presentation, trafficking and retrieval of sybII during the fusion and endocytosis of SVs. The nerve terminal protein α-synuclein catalyses sybII entry into SNARE complexes, whereas the monomeric adaptor protein AP180 is required for sybII retrieval during SV endocytosis. Overarching these events is the tetraspan SV protein synaptophysin, which is a major sybII interaction partner on the SV. This review will evaluate recent studies to propose working models for the control of sybII traffic by synaptophysin and other sybtraps (sybII trafficking partners) and suggest how dysfunction in sybII traffic may contribute to human disease.
    Traffic 11/2013;
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    ABSTRACT: Effective relief from chronic hypersensitive pain states remains an unmet need. Here we report the discovery that the TRPM8 ion channel, co-operating with the 5-HT1B receptor (5-HT1BR) in a subset of sensory afferents, exerts an influence at the spinal cord level to suppress central hypersensitivity in pain processing throughout the central nervous system. Using cell line models, ex vivo rat neural tissue and in vivo pain models, we assessed functional Ca(2+) fluorometric responses, protein:protein interactions, immuno-localisation and reflex pain behaviours, with pharmacological and molecular interventions. We report 5-HT1BR expression in many TRPM8-containing afferents and direct interaction of these proteins in a novel multi-protein signalling complex, which includes phospholipase D1 (PLD1). We provide evidence that the 5-HT1BR activates PLD1 to subsequently activate PIP 5-kinase and generate PIP2, an allosteric enhancer of TRPM8, achieving a several-fold increase in potency of TRPM8 activation. The enhanced activation responses of synaptoneurosomes prepared from spinal cord and cortical regions of animals with a chronic inflammatory pain state are inhibited by TRPM8 activators that were applied in vivo topically to the skin, an effect potentiated by co-administered 5-HT1BR agonists and attenuated by 5-HT1BR antagonists, while 5-HT1BR agents alone had no detectable effect. Corresponding results are seen when assessing reflex behaviours in inflammatory and neuropathic pain models. Control experiments with alternative receptor/TRP channel combinations reveal no such synergy. Identification of this novel receptor/effector/channel complex and its impact on nociceptive processing give new insights into possible strategies for enhanced analgesia in chronic pain.
    Neuropharmacology 11/2013;
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    ABSTRACT: Reporting in Developmental Cell, Packard et al. (2013) identify a peculiar mitotic behavior in ureteric bud tips whereby dividing cells leave the epithelium for the lumen, retaining only a slender connection with basement membrane. One daughter inherits its mother's location, whereas the other moves along the lumen and reintegrates there.
    Developmental Cell 11/2013; 27(3):245-246.
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    ABSTRACT: Pharmacology and regenerative medicine interact in two ways. One is the use of drugs to promote tissue regeneration. The other, less obvious but with great potential, is the use of techniques developed for regenerative medicine to engineer realistic human organoids for drug screening. This review focuses on testing for nephrotoxicity, often a problem with drugs and poorly predicted in animals. Current human-based screens mainly use proximal tubule cells growing in 2D monolayers. Realism might be improved by collagen-based culture systems that encourage proximal tubule cells to grow as tubules. More realistic would be a recently developed technique for engineering functioning 'mini-kidneys' from suspensions of stem cells, a technique that works in mouse but that could also be applied to humans.
    Drug discovery today 11/2013;
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    ABSTRACT: The corticothalamic and thalamocortical tracts play essential roles in the communication between the cortex and thalamus. During development, axons forming these tracts have to follow a complex path to reach their target areas. While much attention has been paid to the mechanisms regulating their passage through the ventral telencephalon, very little is known about how the developing cortex contributes to corticothalamic/thalamocortical tract formation. Gli3 encodes a zinc finger transcription factor widely expressed in telencephalic progenitors which has important roles in corticothalamic and thalamocortical pathfinding. Here, we conditionally inactivated Gli3 in dorsal telencephalic progenitors to determine its role in corticothalamic tract formation. In Emx1Cre;Gli3(fl/fl) mutants, only a few corticothalamic axons enter the striatum in a restricted dorsal domain. This restricted entry correlates with a medial expansion of the piriform cortex. Transplantation experiments showed that the expanded piriform cortex repels corticofugal axons. Moreover, expression of Sema5B, a chemorepellent for corticofugal axons produced by the piriform cortex, is similarly expanded. Finally, time course analysis revealed an expansion of the ventral pallial progenitor domain which gives rise to the piriform cortex. Hence, control of lateral cortical development by Gli3 at the progenitor level is crucial for corticothalamic pathfinding.
    Cerebral Cortex 09/2013;
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    ABSTRACT: Radial glia of the mouse cerebral cortex emerge from neuroepithelial stem cells around embryonic day 11 and produce excitatory cortical neurons until a few days before birth. The molecular mechanisms that regulate the end of cortical neurogenesis remain largely unknown. Here we investigated if the Dicer-dependent microRNA (miRNA) pathway is involved. By electroporating a cre-recombinase expression vector into the cortex of E13.5 embryos carrying a conditional allele of Dicer1, we induced mosaic recombination causing Dicer1 deletion and reporter activation in a subset of radial glia. We analyzed the long-term fates of their progeny. We found that mutant radial glia produced abnormally large numbers of Cux1-positive neurons, many of which populated the superficial cortical layers. Injections of the S-phase marker bromodeoxyuridine between postnatal days 3 and 14 showed that much of this population was generated postnatally. Our findings suggest a role for Dicer-dependent processes in limiting the timespan of cortical neurogenesis.
    Developmental Biology 09/2013;
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    ABSTRACT: Objectives:To investigate the effect of obesity in early-mid pregnancy on crucial pregnancy hormones and the uterine immune environment.Background:Obesity impacts reproductive ability, adversely affecting conception and leading to complications in pregnancy. Obesity is often regarded as a stress state and an immune disease, both of which may contribute to pregnancy failure. We previously demonstrated that stress in early pregnancy greatly alters progesterone secretion. As progesterone is an immunomodulator, altered progesterone secretion may adversely modify the maternal immune system. In the current study, we test the hypothesis that obesity during pregnancy adversely alters the uterine immune environment.Methods:An obese mouse model was created by feeding C57/BL6 mice on a high-fat (HF)/sugar diet for 12 weeks before pregnancy. Control mice were fed on lower-fat/sugar chow. Mice were mated, and on day 7.5 of pregnancy plasma progesterone and prolactin were measured by immunoassay. Cells from the uterus-draining inguinal lymph nodes were collected for analysis of the uterine immune response by flow cytometry.Results:Diet-induced obesity increased the secretion of progesterone and altered a number of uterine natural killer (NK)- and T-cell responses. These included a marked reduction in the percentage of leucocyte-derived NK cells and reduced expression of interferon-γ (IFN-γ) in the NK cells compared with control mice.Conclusions:Maternal obesity, induced by an HF diet, may lead to a reduction in the expression of IFN-γ in NK cells. NK-cell-derived IFN-γ is reported to be involved in supporting uterine spiral artery remodelling. Thus, obesity in early pregnancy may compromise vascularization by reducing the expression of IFN-γ-positive NK cells. Furthermore, the expression of uterine CD8(+) cells was reduced in the HF diet-fed mice, suggesting obesity may adversely alter the maternal immune adaptation that is essential for effective pregnancy.International Journal of Obesity advance online publication, 1 October 2013; doi:10.1038/ijo.2013.164.
    International journal of obesity (2005) 09/2013;
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    ABSTRACT: Signalling cascades control multiple aspects of presynaptic function. Synaptic vesicle endocytosis was assumed to be exempt from modulation, due to its essential role maintaining synaptic vesicle supply and thus neurotransmission. Here we show that brain-derived neurotrophic factor arrests the rephosphorylation of the endocytosis enzyme dynamin I via an inhibition of glycogen synthase kinase 3. This event results in a selective inhibition of activity-dependent bulk endocytosis during high-intensity firing. Furthermore, the continued presence of brain-derived neurotrophic factor alleviates the rundown of neurotransmission during high activity. Thus, synaptic strength can be modulated by extracellular signalling molecules via a direct inhibition of a synaptic vesicle endocytosis mode.
    Nature Communications 09/2013; 4:2394.
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