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Neuron and mTOR

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https://www.readbyqxmd.com/read/29051493/variation-in-a-range-of-mtor-related-genes-associates-with-intracranial-volume-and-intellectual-disability
#1
M R F Reijnders, M Kousi, G M van Woerden, M Klein, J Bralten, G M S Mancini, T van Essen, M Proietti-Onori, E E J Smeets, M van Gastel, A P A Stegmann, S J C Stevens, S H Lelieveld, C Gilissen, R Pfundt, P L Tan, T Kleefstra, B Franke, Y Elgersma, N Katsanis, H G Brunner
De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype...
October 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/29049987/isoflavones-induce-bex2-dependent-autophagy-to-prevent-atr-induced-neurotoxicity-in-sh-sy5y-cells
#2
Peng Li, Kun Ma, Hao-Yu Wu, Yan-Ping Wu, Bai-Xiang Li
BACKGROUND/AIMS: Atrazine (ATR) is a broad-spectrum herbicide in wide use around the world. However, ATR is neurotoxic and can cause cell death in dopaminergic neurons, leading to neurodegenerative disorders. Autophagy is the basic cellular catabolic process involving the degradation of proteins and damaged organelles. Studies have shown that certain plant compounds can induce autophagy and prevent neuronal cell death. This prompted us to investigate plant compounds that might reduce the neurotoxic effects of ATR...
October 19, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29039596/the-role-of-the-mir-99b-5p-mtor-signaling-pathway-in-neuroregeneration-in-mice-following-spinal-cord-injury
#3
Fujiang Cao, Tao Liu, Shiwei Sun, Shiqing Feng
The present study aimed to investigate the role of microRNA (miR)‑99b‑5p in spinal cord injury (SCI). Reverse transcription‑quantitative polymerase chain reaction demonstrated that, compared with control mice, the expression levels of miR‑99b‑5p were upregulated in the mouse spinal cord following SCI. Mechanistic target of rapamycin (mTOR) was predicted to be the possible target of miR‑99b‑5p according to TargetScan and microrna databases. Dual‑luciferase reporter assay verified that miR‑99b‑5p was able to target mTOR...
October 17, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29039413/vta-mtor-signaling-regulates-dopamine-dynamics-cocaine-induced-synaptic-alterations-and-reward
#4
Xiaojie Liu, Yan Li, Laikang Yu, Casey R Vickstrom, Qing-Song Liu
Mechanistic target of rapamycin (mTOR) regulates long-term synaptic plasticity, learning and memory by controlling dendritic protein synthesis. The mTOR inhibitor rapamycin has been shown to attenuate the behavioral effects of drugs of abuse, including cocaine. Using viral vectors to selectively delete mTOR in the ventral tegmental area (VTA) in adult male mTOR(loxP/loxP) mice, we investigated the role of mTOR in regulating neuronal morphology, basal synaptic transmission, dopamine dynamics and cocaine-induced synaptic plasticity and rewarding effects...
October 17, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29027613/both-decreased-akt-expression-and-mtor-phosphorylation-are-related-to-decreased-neuronal-differentiation-in-the-hippocampal-alveus-of-aged-mice
#5
Bing Chun Yan, Dan Jiang, Jie Wang, Yuanyuan Zhang, Xiaolu Zhu, Pei Xu, Xing Yu, Moo-Ho Won, Pei Qing Su
BACKGROUND: Aging is an inevitable process which results in many changes. These changes are closely related to the hippocampus which is in charge of long-term learning and episodic memory. AIM: This study was to investigate age-related changes of the cell proliferation, neuroblast differentiation and Akt/mTOR signaling in the hippocampal alveus of aged mice. METHODS: In the present study, we compared the differences of neurogenesis in the hippocampal alveus between adult (postnatal month 6) and aged (postnatal month 24) mice using immunohistochemistry and western blot analysis...
October 13, 2017: Aging Clinical and Experimental Research
https://www.readbyqxmd.com/read/29025974/lipid-based-dna-sirna-transfection-agents-disrupt-neuronal-bioenergetics-and-mitophagy
#6
Eleonora Napoli, Siming Liu, Ilaria Marsilio, Konstantinos Zarbalis, Cecilia Giulivi
A multitude of natural and artificial compounds have been recognized to modulate autophagy, providing direct or, through associated pathways, indirect entry points to activation and inhibition. While these pharmacological tools are extremely useful in the study of autophagy, their abundance also suggests the potential presence of unidentified autophagic modulators that may interfere with experimental designs if applied unknowingly. Here, we report unanticipated effects on autophagy and bioenergetics in neuronal progenitor cells (NPC) incubated with widely used lipid-based-transfection reagent lipofectamine (LF), which induced mitochondria depolarization followed by disruption of electron transport...
October 12, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29023667/postnatal-reduction-of-tuberous-sclerosis-complex-1-expression-in-astrocytes-and-neurons-causes-seizures-in-an-age-dependent-manner
#7
Jia Zou, Bo Zhang, David H Gutmann, Michael Wong
OBJECTIVE: Epilepsy is one of the most prominent symptoms of tuberous sclerosis complex (TSC), a genetic disorder, and may be related to developmental defects resulting from impaired TSC1 or TSC2 gene function in astrocytes and neurons. Inactivation of the Tsc1 gene driven by a glial-fibrillary acidic protein (GFAP) promoter during embryonic brain development leads to widespread pathologic effects on astrocytes and neurons, culminating in severe, progressive epilepsy in mice (Tsc1(GFAP)(-Cre) mice)...
October 12, 2017: Epilepsia
https://www.readbyqxmd.com/read/28990517/anesthetic-agents-and-neuronal-autophagy-what-we-know-and-what-we-don-t
#8
Lili Xu, Jianjun Shen, Patrick M McQuillan, Zhiyong Hu
Numerous experimental data have demonstrated that neonatal animal exposure to commonly used anesthetic agents may cause neuronal death resulting in cognitive impairment. The underlying mechanism(s) remain elusive. Depending on the circumstances, autophagy may produce an effect that can be either protective or deleterious. Recent evidence demonstrates that this process can reduce the development of ethanol induced neurotoxicity and, as we know, ethanol has γ-Aminobutyric acid (GABA) agonist and N-methyl-D-aspartate (NMDA) antagonist characteristics similar to commonly used volatile anesthetic agents...
October 9, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28986235/alpha-synuclein-epigenetics-mitochondria-metabolism-calcium-traffic-circadian-dysfunction-in-parkinson-s-disease-an-integrated-strategy-for-management
#9
REVIEW
Oliver T Phillipson
The motor deficits which characterise the sporadic form of Parkinson's disease arise from age-related loss of a subset of dopamine neurons in the substantia nigra. Although motor symptoms respond to dopamine replacement therapies, the underlying disease process remains. This review details some features of the progressive molecular pathology and proposes deployment of a combination of nutrients: R-lipoic acid, acetyl-l-carnitine, ubiquinol, melatonin (or receptor agonists) and vitamin D3, with the collective potential to slow progression of these features...
October 3, 2017: Ageing Research Reviews
https://www.readbyqxmd.com/read/28980850/rilmenidine-promotes-mtor-independent-autophagy-in-the-mutant-sod1-mouse-model-of-amyotrophic-lateral-sclerosis-without-slowing-disease-progression
#10
Nirma D Perera, Rebecca K Sheean, Chew L Lau, Yea Seul Shin, Philip M Beart, Malcolm K Horne, Bradley J Turner
Macroautophagy/autophagy is the main intracellular catabolic pathway in neurons that eliminates misfolded proteins, aggregates and damaged organelles associated with ageing and neurodegeneration. Autophagy is regulated by both MTOR-dependent and -independent pathways. There is increasing evidence that autophagy is compromised in neurodegenerative disorders, which may contribute to cytoplasmic sequestration of aggregation-prone and toxic proteins in neurons. Genetic or pharmacological modulation of autophagy to promote clearance of misfolded proteins may be a promising therapeutic avenue for these disorders...
October 5, 2017: Autophagy
https://www.readbyqxmd.com/read/28970178/autophagy-mediated-neuroprotection-induced-by-octreotide-in-an-ex-vivo-model-of-early-diabetic-retinopathy
#11
Rosario Amato, Elisabetta Catalani, Massimo Dal Monte, Maurizio Cammalleri, Ilaria Di Renzo, Cristiana Perrotta, Davide Cervia, Giovanni Casini
Neuronal injury plays a major role in diabetic retinopathy (DR). Our hypothesis was that the balance between neuronal death and survival may depend on a similar equilibrium between apoptosis and autophagy and that a neuroprotectant may act by influencing this equilibrium. Ex vivo mouse retinal explants were treated with high glucose (HG) for 10days and the somatostatin analog octreotide (OCT) was used as a neuroprotectant. Chloroquine (CQ) was used as an autophagy inhibitor. Apoptotic and autophagic markers were evaluated using western blot and immunohistochemistry...
September 29, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28969943/deciphering-the-pathways-that-protect-from-il-13-mediated-potentiation-of-oxidative-stress-induced-dopaminergic-nerve-cell-death
#12
Pamela Maher, Bruno Conti
The majority of Parkinson's disease (PD) cases are sporadic with only about 10% of PD patients having a family history of the disease suggesting that this neurodegenerative disorder is the result of both environmental and genetic factors. Both oxidative stress and neuroinflammation are thought to contribute to PD. Previously, we showed that the activation of interleukin 13 receptor alpha 1 (IL-13Rα1) increases the sensitivity of dopaminergic neurons to oxidative damage both in cultured cells and in animals...
September 30, 2017: Cytokine
https://www.readbyqxmd.com/read/28967557/combining-constitutively-active-rheb-expression-and-chondroitinase-promotes-functional-axonal-regeneration-after-cervical-spinal-cord-injury
#13
Di Wu, Michelle C Klaw, Theresa Connors, Nikolai Kholodilov, Robert E Burke, Marie-Pascale Côté, Veronica J Tom
After spinal cord injury (SCI), severed axons in the adult mammalian CNS are unable to mount a robust regenerative response. In addition, the glial scar at the lesion site further restricts the regenerative potential of axons. We hypothesized that a combinatorial approach coincidentally targeting these obstacles would promote axonal regeneration. We combined (1) transplantation of a growth-permissive peripheral nerve graft (PNG) into an incomplete, cervical lesion cavity; (2) transduction of neurons rostral to the SCI site to express constitutively active Rheb (caRheb; a Ras homolog enriched in brain), a GTPase that directly activates the growth-promoting pathway mammalian target of rapamycin (mTOR) via AAV-caRheb injection; and (3) digestion of growth-inhibitory chondroitin sulfate proteoglycans within the glial scar at the distal PNG interface using the bacterial enzyme chondroitinase ABC (ChABC)...
August 19, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28966575/pi3k-mtor-s6k-signaling-mediates-neuronal-viability-via-collapsin-response-mediator-protein-2-expression
#14
Eun J Na, Hye Yeon Nam, Jiyoung Park, Myung Ah Chung, Hyun Ae Woo, Hwa-Jung Kim
Collapsin response mediator protein (CRMP)-2 and the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway are associated with common physiological functions such as neuronal polarity, axonal outgrowth and synaptic strength, as well as various brain disorders including epilepsy. But, their regulatory and functional links are unclear. Alterations in CRMP-2 expression that lead to its functional changes are implicated in brain disorders such as epilepsy. Here, we investigate whether changes in CRMP-2 expression, possibly regulated by mTOR-related signaling, correlates with neuronal growth and viability...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28965934/the-activation-of-autophagy-protects-neurons-and-astrocytes-against-bilirubin-induced-cytotoxicity
#15
Mohammed Qaisiya, Paula Mardešić, Beatrice Pastore, Claudio Tiribelli, Cristina Bellarosa
Unconjugated bilirubin (UCB) neurotoxicity involves oxidative stress, calcium signaling and ER-stress. The same insults can also induce autophagy, a process of "self-eating", with both a pro-survival or a pro-apoptotic role. Our aim was to study the outcome of autophagy activation by UCB in the highly sensitive neuronal SH-SY5Y cells and in the resistant astrocytoma U87 cells. Upon treatment with a toxic dose of UCB, the conversion of LC3-I to LC3-II was detected in both cell lines. Inhibition of autophagy by E64d before UCB treatment increased SH-SY5Y cell mortality and made U87 cells sensitive to UCB...
September 28, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28965829/reduced-brain-insulin-signaling-a-seminal-process-in-alzheimer-s-disease-pathogenesis
#16
REVIEW
George S Bloom, John S Lazo, Andrés Norambuena
The synaptic dysfunction and death of neurons that mediate memory and cognition account together for the behavioral symptoms of Alzheimer's disease (AD). Reduced insulin signaling in the brain is a hallmark of AD patients, even in the absence of systemic type 1 or type 2 diabetes, prompting some researchers to refer to AD as brain-specific, or type 3 diabetes. A key question that arises about this signature feature of AD is "how, if at all, does the brain's impaired ability to utilize insulin contribute to the behavioral deficits associated with AD?" The fact that type 2 diabetes is a risk factor for AD suggests a causative role for impaired insulin responsiveness in AD pathogenesis, but how that might occur at a detailed molecular level had been elusive...
September 29, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28959975/targeting-neuronal-activity-regulated-neuroligin-3-dependency-in-high-grade-glioma
#17
Humsa S Venkatesh, Lydia T Tam, Pamelyn J Woo, James Lennon, Surya Nagaraja, Shawn M Gillespie, Jing Ni, Damien Y Duveau, Patrick J Morris, Jean J Zhao, Craig J Thomas, Michelle Monje
High-grade gliomas (HGG) are a devastating group of cancers, and represent the leading cause of brain tumour-related death in both children and adults. Therapies aimed at mechanisms intrinsic to glioma cells have translated to only limited success; effective therapeutic strategies will need also to target elements of the tumour microenvironment that promote glioma progression. Neuronal activity promotes the growth of a range of molecularly and clinically distinct HGG types, including adult and paediatric glioblastoma (GBM), anaplastic oligodendroglioma, and diffuse intrinsic pontine glioma (DIPG)...
September 28, 2017: Nature
https://www.readbyqxmd.com/read/28955722/the-progestin-receptor-interactome-in-the-female-mouse-hypothalamus-interactions-with-synaptic-proteins-are-isoform-specific-and-ligand-dependent
#18
Kalpana D Acharya, Sabin A Nettles, Katherine J Sellers, Dana D Im, Moriah Harling, Cassandra Pattanayak, Didem Vardar-Ulu, Cheryl F Lichti, Shixia Huang, Dean P Edwards, Deepak P Srivastava, Larry Denner, Marc J Tetel
Progestins bind to the progestin receptor (PR) isoforms, PR-A and PR-B, in brain to influence development, female reproduction, anxiety, and stress. Hormone-activated PRs associate with multiple proteins to form functional complexes. In the present study, proteins from female mouse hypothalamus that associate with PR were isolated using affinity pull-down assays with glutathione S-transferase-tagged mouse PR-A and PR-B. Using complementary proteomics approaches, reverse phase protein array (RPPA) and mass spectrometry, we identified hypothalamic proteins that interact with PR in a ligand-dependent and isoform-specific manner and were confirmed by Western blot...
September 2017: ENeuro
https://www.readbyqxmd.com/read/28947966/tnf%C3%AE-affects-creb-mediated-neuroprotective-signaling-pathways-of-synaptic-plasticity-in-neurons-as-revealed-by-proteomics-and-phospho-proteomics
#19
Pia Jensen, Christa L Myhre, Pernille S Lassen, Athanasios Metaxas, Asif M Khan, Kate L Lambertsen, Alicia A Babcock, Bente Finsen, Martin R Larsen, Stefan J Kempf
Neuroinflammation is a hallmark of Alzheimer's disease and TNFα as the main inducer of neuroinflammation has neurodegenerative but also pro-regenerative properties, however, the dose-dependent molecular changes on signaling pathway level are not fully understood. We performed quantitative proteomics and phospho-proteomics to target this point. In HT22 cells, we found that TNFα reduced mitochondrial signaling and inhibited mTOR protein translation signaling but also led to induction of neuroprotective MAPK-CREB signaling...
September 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28943602/deltamethrin-increases-neurite-outgrowth-in-cortical-neurons-through-endogenous-bdnf-trkb-pathways
#20
Daisuke Ihara, Mamoru Fukuchi, Momoko Katakai, Yo Shinoda, Ritsuko Katoh-Semba, Teiichi Furuichi, Mitsuru Ishikawa, Akiko Tabuchi, Masaaki Tsuda
Deltamethrin (DM), a type II pyrethroid, robustly increases brain-derived neurotrophic factor (Bdnf) expression and has a neurotrophic effect in primary cultures of rat cortical neurons. In this study, we investigated the effect of DM on neurite morphology in cultured rat cortical neurons. DM significantly increased neurite outgrowth, but this increase was abolished when the BDNF scavenger tropomyosin receptor kinase B (TrkB)-Fc was added 10 min before the DM treatment. In contrast, the addition of TrkB-Fc 1 h after the treatment did not affect DM-induced neurite outgrowth...
September 23, 2017: Cell Structure and Function
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