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mTOR in neuron

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https://www.readbyqxmd.com/read/28068606/trehalose-does-not-improve-neuronal-survival-on-exposure-to-alpha-synuclein-pre-formed-fibrils
#1
Matthew Redmann, Willayat Y Wani, Laura Volpicelli-Daley, Victor Darley-Usmar, Jianhua Zhang
Parkinson's disease is a debilitating neurodegenerative disorder that is pathologically characterized by intracellular inclusions comprised primarily of alpha-synuclein (αSyn) that can also be transmitted from neuron to neuron. Several lines of evidence suggest that these inclusions cause neurodegeneration. Thus exploring strategies to improve neuronal survival in neurons with αSyn aggregates is critical. Previously, exposure to αSyn pre-formed fibrils (PFFs) has been shown to induce aggregation of endogenous αSyn resulting in cell death that is exacerbated by either starvation or inhibition of mTOR by rapamycin, both of which are able to induce autophagy, an intracellular protein degradation pathway...
January 3, 2017: Redox Biology
https://www.readbyqxmd.com/read/28063882/mice-lacking-grip1-2-show-increased-social-interactions-and-enhanced-phosphorylation-at-glua2-s880
#2
Mei Han, Rebeca Mejias, Shu-Ling Chiu, Rebecca Rose, Abby Adamczyk, Richard Huganir, Tao Wang
Glutamate receptor interacting proteins 1 and 2 (GRIP1/2) play an important role in regulating synaptic trafficking of AMPA receptor 2/3 (GluA2/3) and synaptic strength. Gain-of-function GRIP1 mutations are implicated in social behavioral deficits in autism. To study mechanisms of Grip1/2-mediated AMPA signaling in the regulation of social behaviors, we performed social behavioral testing on neuron-specific Grip1/2-double knockout (DKO) and wild type (WT) mice that are matched for age, sex, and strain background...
January 4, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28062257/liraglutide-prevents-cognitive-decline-in-a-rat-model-of-streptozotocin-induced-diabetes-independently-from-its-peripheral-metabolic-effects
#3
Caterina Palleria, Antonio Leo, Francesco Andreozzi, Rita Citraro, Michelangelo Iannone, Rosangela Spiga, Giorgio Sesti, Andrew Constanti, Giovambattista De Sarro, Franco Arturi, Emilio Russo
Diabetes has been identified as a risk factor for cognitive dysfunctions. Glucagone like peptide 1 (GLP-1) receptor agonists have neuroprotective effects in preclinical animal models. We evaluated the effects of GLP-1 receptor agonist, liraglutide (LIR), on cognitive decline associated with diabetes. Furthermore, we studied LIR effects against hippocampal neurodegeneration induced by streptozotocin (STZ), a well-validated animal model of diabetes and neurodegeneration associated with cognitive decline. Diabetes and/or cognitive decline were induced in Wistar rats by intraperitoneal or intracerebroventricular injection of STZ and then rats were treated with LIR (300μg/kg daily subcutaneously) for 6 weeks...
January 3, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28056425/fcd-type-ii-and-mtor-pathway-evidence-for-different-mechanisms-involved-in-the-pathogenesis-of-dysmorphic-neurons
#4
Laura Rossini, Flavio Villani, Tiziana Granata, Laura Tassi, Giovanni Tringali, Francesco Cardinale, Eleonora Aronica, Roberto Spreafico, Rita Garbelli
Type II focal cortical dysplasia (FCD II) is a malformation of cortical development, frequently associated with intractable epilepsy, characterised by cortical dyslamination, dysmorphic neurons (DNs) and balloon cells (BCs). We investigated the expression of pS6 (downstream target) and pPDK1-pAkt (upstream targets) as evidence for mTOR pathway activation and their co-expression with Interleukin-1β in FCD II surgical specimens and compared the findings with control non-epileptic tissue, non-malformed epileptic tissue or acquired epilepsy-Rasmussen's Encephalitis (RE) occasionally presenting pS6 and Interleukin-1β positive abnormal neurons...
December 7, 2016: Epilepsy Research
https://www.readbyqxmd.com/read/28055974/glutamate-induces-autophagy-via-the-two-pore-channels-in-neural-cells
#5
Gustavo J S Pereira, Manuela Antonioli, Hanako Hirata, Rodrigo P Ureshino, Aline R Nascimento, Claudia Bincoletto, Tiziana Vescovo, Mauro Piacentini, Gian Maria Fimia, Soraya S Smaili
NAADP (nicotinic acid adenine dinucleotide phosphate) has been proposed as a second messenger for glutamate in neuronal and glial cells via the activation of the lysosomal Ca2+ channels TPC1 and TPC2. However, the activities of glutamate that are mediated by NAADP remain unclear. In this study, we evaluated the effect of glutamate on autophagy in astrocytes at physiological, non-toxic concentration. We found that glutamate induces autophagy at similar extent as NAADP. By contrast, the NAADP antagonist NED-19 or SiRNA-mediated inhibition of TPC1/2 decreases autophagy induced by glutamate, confirming a role for NAADP in this pathway...
December 31, 2016: Oncotarget
https://www.readbyqxmd.com/read/28042771/oxidative-stress-pro-inflammatory-cytokines-and-antioxidants-regulate-expression-levels-of-micrornas-in-parkinson-s-disease
#6
Kedar N Prasad
Parkinson's disease (PD) is a slow progressive neurodegenerative disease associated with abnormal function of extrapyramidal system. Although several biochemical and genetic defects have been identified, increased oxidative stress and chronic inflammation are one of the earliest events that initiate and promote PD. Oxidative stress also participates in impaired non-motor symptoms.The levels of microRNAs that are evolutionarily conserved single-stranded non-coding RNAs of approximately 22 nucleotide in length are altered in PD...
January 2, 2017: Current Aging Science
https://www.readbyqxmd.com/read/28042028/urb597-improves-cognitive-impairment-induced-by-chronic-cerebral-hypoperfusion-by-inhibiting-mtor-dependent-autophagy
#7
Dapeng Wang, Qi Lin, Shaohua Su, Kejia Liu, Yifang Wu, Jian Hai
Chronic cerebral hypoperfusion (CCH) is associated with various ischemic cerebrovascular diseases that are characterized by cognitive impairment. The role of autophagy in cognitive dysfunction under conditions of CCH is poorly understood. To address this issue, the present study investigated the effect of the fatty acid amide hydrolase (FAAH) inhibitor URB597 on autophagy and cognition in a CCH model as well as the underlying mechanisms. Cognitive function was evaluated with the Morris water maze and by assessing long-term potentiation (LTP)...
December 30, 2016: Neuroscience
https://www.readbyqxmd.com/read/28035937/mtorc2-rictor-in-alzheimer-s-disease-and-reversal-of-amyloid-%C3%AE-expression-induced-insulin-resistance-and-toxicity-in-rat-primary-cortical-neurons
#8
Han-Kyu Lee, Bumsup Kwon, Cynthia A Lemere, Suzanne de la Monte, Kyohei Itamura, Austin Y Ha, Henry W Querfurth
Mammalian target of rapamycin complex 1 (mTORC1), a nutrient sensor and central controller of cell growth and proliferation, is altered in various models of Alzheimer's disease (AD). Even less studied or understood in AD is mammalian target of rapamycin complex 2 (mTORC2) that influences cellular metabolism, in part through the regulations of Akt/PKB and SGK. Dysregulation of insulin/PI3K/Akt signaling is another important feature of AD pathogenesis. We found that both total mTORC1 and C2 protein levels and individual C1 and C2 enzymatic activities were decreased in human AD brain samples...
December 30, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28035406/bambi-inhibits-inflammation-through-the-activation-of-autophagy-in-experimental-spinal-cord-injury
#9
Yin Yang, Chunyang Guo, Bo Liao, Junjun Cao, Chen Liang, Xijing He
Autophagy plays an important role in the progression of spinal cord injury (SCI). In this study, we aimed to examine the effects and potential mechanisms of action of BMP and activin membrane-bound inhibitor (BAMBI) in the progression of SCI. A rat model of SCI was established and the rats were injected with pLentiH1-BAMBI shRNA and pAd-BAMBI in the gray and white matter of the spinal cord at T8. After 14 days, motor function evaluation was measured according to the Basso Beattie Bresnahan (BBB) method and the number of motor neuron cell accounts in the anterior horns was measured by Nissl staining...
December 27, 2016: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28027414/roles-of-p62-in-bdnf-dependent-autophagy-suppression-and-neuroprotection-against-mitochondrial-dysfunction-in-rat-cortical-neurons
#10
Chia-Lin Wu, Chien-Hui Chen, Chi-Shin Hwang, Shang-Der Chen, Wei-Chao Hwang, Ding-I Yang
Previously we have reported that preconditioning of primary rat cortical neurons with brain-derived neurotrophic factor (BDNF) may exert neuroprotective effects against 3-nitropropionic acid (3-NP), a mitochondrial complex II inhibitor. However, the underlying mechanisms, especially potential involvements of autophagy, remain elusive. In this work, we tested the hypothesis that BDNF may suppress 3-NP-induced autophagy to exert its neuroprotective effects by inducing the expression of p62/sequestosome-1 in primary cortical neurons...
December 27, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28017716/effects-of-learning-on-mtor-pathway-gene-expression-in-the-brain-of-zebrafish-danio-rerio-of-different-ages
#11
Carolina da Silva Peixoto, Gustavo Morrone Parfitt, Gisele Eva Bruch, Marcos Freitas Cordeiro, Daniela Volcan Almeida, Luis Fernando Fernandes Marins, Daniela Martí Barros
Target of rapamycin (TOR) is a protein kinase involved in the modulation of mRNA translation and, therefore, in the regulation of protein synthesis. In neurons, the role of TOR is particularly important in the consolidation of long-term memory (LTM). One of the modulators of TOR is brain-derived neurotrophic factor (BDNF), which activates the TOR signaling pathway to promote protein synthesis, synapse strengthening, and the creation of new neural networks. We investigated the gene expression pattern of this pathway during memory consolidation in zebrafish of different ages...
December 22, 2016: Experimental Gerontology
https://www.readbyqxmd.com/read/28017472/loss-of-nardilysin-a-mitochondrial-co-chaperone-for-%C3%AE-ketoglutarate-dehydrogenase-promotes-mtorc1-activation-and-neurodegeneration
#12
Wan Hee Yoon, Hector Sandoval, Sonal Nagarkar-Jaiswal, Manish Jaiswal, Shinya Yamamoto, Nele A Haelterman, Nagireddy Putluri, Vasanta Putluri, Arun Sreekumar, Tulay Tos, Ayse Aksoy, Taraka Donti, Brett H Graham, Mikiko Ohno, Eiichiro Nishi, Jill Hunter, Donna M Muzny, Jason Carmichael, Joseph Shen, Valerie A Arboleda, Stanley F Nelson, Michael F Wangler, Ender Karaca, James R Lupski, Hugo J Bellen
We previously identified mutations in Nardilysin (dNrd1) in a forward genetic screen designed to isolate genes whose loss causes neurodegeneration in Drosophila photoreceptor neurons. Here we show that NRD1 is localized to mitochondria, where it recruits mitochondrial chaperones and assists in the folding of α-ketoglutarate dehydrogenase (OGDH), a rate-limiting enzyme in the Krebs cycle. Loss of Nrd1 or Ogdh leads to an increase in α-ketoglutarate, a substrate for OGDH, which in turn leads to mTORC1 activation and a subsequent reduction in autophagy...
January 4, 2017: Neuron
https://www.readbyqxmd.com/read/28011637/tribbles-pseudokinase-3-induces-both-apoptosis-and-autophagy-in-amyloid-%C3%AE-induced-neuronal-death
#13
Suraiya Saleem, Subhas Chandra Biswas
Amyloid-β (Aβ) induced neuron death is considered central to the pathogenesis of Alzheimer disease (AD). Among several death modalities, autophagy and apoptosis play important roles in Aβ-induced neuron death suggesting that there may be regulatory mechanisms that initiate both cell death pathways. However, molecules that govern both pathways have not been identified. Here, we report that, upon Aβ treatment, tribbles pseudokinase 3 (TRIB3, an ortholog of Drosophila Tribbles), is upregulated in neurons, both in vivo and in vitro...
December 23, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28008307/specific-metabolomics-adaptations-define-a-differential-regional-vulnerability-in-the-adult-human-cerebral-cortex
#14
Rosanna Cabré, Mariona Jové, Alba Naudí, Victoria Ayala, Gerard Piñol-Ripoll, Maria P Gil-Villar, Mayelin Dominguez-Gonzalez, Èlia Obis, Rebeca Berdun, Natalia Mota-Martorell, Manuel Portero-Otin, Isidre Ferrer, Reinald Pamplona
Brain neurons offer diverse responses to stresses and detrimental factors during development and aging, and as a result of both neurodegenerative and neuropsychiatric disorders. This multiplicity of responses can be ascribed to the great diversity among neuronal populations. Here we have determined the metabolomic profile of three healthy adult human brain regions-entorhinal cortex, hippocampus, and frontal cortex-using mass spectrometry-based technologies. Our results show the existence of a lessened energy demand, mitochondrial stress, and lower one-carbon metabolism (particularly restricted to the methionine cycle) specifically in frontal cortex...
2016: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/27979658/sixty-years-old-is-the-breakpoint-of-human-frontal-cortex-aging
#15
Rosanna Cabré, Alba Naudí, Mayelin Dominguez-Gonzalez, Victòria Ayala, Mariona Jové, Natalia Mota-Martorell, Gerard Piñol-Ripoll, Maria Pilar Gil-Villar, Montserrat Rué, Manuel Portero-Otín, Isidre Ferrer, Reinald Pamplona
Human brain aging is the physiological process which underlies as cause of cognitive decline in the elderly and the main risk factor for neurodegenerative diseases such as Alzheimer's disease. Human neurons are functional throughout a healthy adult lifespan, yet the mechanisms that maintain function and protect against neurodegenerative processes during aging are unknown. Here we show that protein oxidative and glycoxidative damage significantly increases during human brain aging, with a breakpoint at 60 years old...
December 13, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27977864/n-methyl-d-aspartate-nmda-impairs-myogenesis-in-c2c12-cells
#16
Q-Schick Auh, Kyung-Ran Park, Myeong-Ok Lee, Mi-Jin Hwang, Soo-Kyung Kang, Jung-Pyo Hong, Hyung-Mun Yun, Eun-Cheol Kim
INTRODUCTION: N-methyl-d-aspartate (NMDA) is expressed in sensory neurons and plays important roles in peripheral pain mechanisms. The aim of this study was to examine the effects and molecular mechanisms of NMDA on C2C12 myoblast proliferation and differentiation. METHODS: Cytotoxicity and differentiation were examined by the MTT assay, RT-PCR, and immunofluorescence. RESULTS: NMDA had no cytotoxicity (10-500 μM) and inhibited myoblastic differentiation of C2C12 cells, as assessed by F-actin immunofluorescence and levels of mRNAs encoding myogenic markers such as myogenin and myosin heavy-chain 2 (MYH2)...
December 15, 2016: Muscle & Nerve
https://www.readbyqxmd.com/read/27974395/lamins-and-metabolism
#17
REVIEW
Chayki Charar, Yosef Gruenbaum
Lamins are nuclear intermediate filaments (IFs) with important roles in most nuclear activities, including nuclear organization and cell-cycle progression. Mutations in human lamins cause over 17 different diseases, termed laminopathies. Most of these diseases are autosomal dominant and can be roughly divided into four major groups: muscle diseases, peripheral neuronal diseases, accelerated aging disorders and metabolic diseases including Dunnigan type familial partial lipodystrophy (FLPD), acquired partial lipodystrophy (APL) and autosomal dominant leucodystrophy...
January 1, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/27960107/forebrain-depletion-of-rheb-gtpase-elicits-spatial-memory-deficits-in-mice
#18
Neelam Shahani, Wen-Chin Huang, Megan Varnum, Damon T Page, Srinivasa Subramaniam
The precise molecular and cellular events responsible for age-dependent cognitive dysfunctions remain unclear. We report that Rheb (ras homolog enriched in brain) GTPase, an activator of mammalian target of rapamycin (mTOR), regulates memory functions in mice. Conditional depletion of Rheb selectively in the forebrain of mice obtained from crossing Rheb(f/f) and CamKII(Cre) results in spontaneous signs of age-related memory loss, that is, spatial memory deficits (T-maze, Morris water maze) without affecting locomotor (open-field test), anxiety-like (elevated plus maze), or contextual fear conditioning functions...
February 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/27935582/global-ischemia-induces-lysosomal-mediated-degradation-of-mtor-and-activation-of-autophagy-in-hippocampal-neurons-destined-to-die
#19
Jee-Yeon Hwang, Michael Gertner, Fabrizio Pontarelli, Brenda Court-Vazquez, Michael Vander Laan Bennett, Dimitry Ofengeim, Ruth Suzanne Zukin
The mammalian target of rapamycin (mTOR) is a key regulator of cell growth, autophagy, translation, and survival. Dysregulation of mTOR signaling is associated with cancer, diabetes, and autism. However, a role for mTOR signaling in neuronal death is not well delineated. Here we show that global ischemia triggers a transient increase in mTOR phosphorylation at S2448, whereas decreasing p-mTOR and functional activity in selectively vulnerable hippocampal CA1 neurons. The decrease in mTOR coincides with an increase in biochemical markers of autophagy, pS317-ULK-1, pS14-Beclin-1, and LC3-II, a decrease in the cargo adaptor p62, and an increase in autophagic flux, a functional readout of autophagy...
December 9, 2016: Cell Death and Differentiation
https://www.readbyqxmd.com/read/27928028/mitochondrial-pyruvate-carrier-regulates-autophagy-inflammation-and-neurodegeneration-in-experimental-models-of-parkinson-s-disease
#20
Anamitra Ghosh, Trevor Tyson, Sonia George, Erin N Hildebrandt, Jennifer A Steiner, Zachary Madaj, Emily Schulz, Emily Machiela, William G McDonald, Martha L Escobar Galvis, Jeffrey H Kordower, Jeremy M Van Raamsdonk, Jerry R Colca, Patrik Brundin
Mitochondrial and autophagic dysfunction as well as neuroinflammation are involved in the pathophysiology of Parkinson's disease (PD). We hypothesized that targeting the mitochondrial pyruvate carrier (MPC), a key controller of cellular metabolism that influences mTOR (mammalian target of rapamycin) activation, might attenuate neurodegeneration of nigral dopaminergic neurons in animal models of PD. To test this, we used MSDC-0160, a compound that specifically targets MPC, to reduce its activity. MSDC-0160 protected against 1-methyl-4-phenylpyridinium (MPP(+)) insult in murine and cultured human midbrain dopamine neurons and in an α-synuclein-based Caenorhabditis elegans model...
December 7, 2016: Science Translational Medicine
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