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Neurobiology of Disease

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https://www.readbyqxmd.com/read/29341898/induction-of-alpha-synuclein-pathology-in-the-enteric-nervous-system-of-the-rat-and-non-human-primate-results-in-gastrointestinal-dysmotility-and-transient-cns-pathology
#1
Fredric P Manfredsson, Kelvin C Luk, Matthew J Benskey, Aysegul Guezer, Joanna Garcia, Nathan C Kuhn, Ivette M Sandoval, Joseph R Patterson, Alana O'Mara, Reid Yonkers, Jeffrey H Kordower
Alpha-Synuclein (α-syn) is by far the most highly vetted pathogenic and therapeutic target in Parkinson's disease. Aggregated α-syn is present in sporadic Parkinson's disease, both in the central nervous system (CNS) and peripheral nervous system (PNS). The enteric division of the PNS is of particular interest because 1) gastric dysfunction is a key clinical manifestation of Parkinson's disease, and 2) Lewy pathology in myenteric and submucosal neurons of the enteric nervous system (ENS) has been referred to as stage zero in the Braak pathological staging of Parkinson's disease...
January 13, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29337050/impairments-in-social-novelty-recognition-and-spatial-memory-in-mice-with-conditional-deletion-of-scn1a-in-parvalbumin-expressing-cells
#2
Tetsuya Tatsukawa, Ikuo Ogiwara, Emi Mazaki, Atsushi Shimohata, Kazuhiro Yamakawa
Loss of function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel Nav1.1, have been described in the majority of Dravet syndrome patients presenting with epileptic seizures, hyperactivity, autistic traits, and cognitive decline. We previously reported predominant Nav1.1 expression in parvalbumin-expressing (PV+) inhibitory neurons in juvenile mouse brain and observed epileptic seizures in mice with selective deletion of Scn1a in PV+ cells mediated by PV-Cre transgene expression (Scn1afl/+/PV-Cre-TG)...
January 11, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29331264/altered-levels-of-the-splicing-factor-muscleblind-modifies-cerebral-cortical-function-in-mouse-models-of-myotonic-dystrophy
#3
Gang Chen, Russell E Carter, John D Cleary, Tammy S Reid, Laura P Ranum, Maurice S Swanson, Timothy J Ebner
Myotonic dystrophy (DM) is a progressive, multisystem disorder affecting skeletal muscle, heart, and central nervous system. In both DM1 and DM2, microsatellite expansions of CUG and CCUG RNA repeats, respectively, accumulate and disrupt functions of alternative splicing factors, including muscleblind (MBNL) proteins. Grey matter loss and white matter changes, including the corpus callosum, likely underlie cognitive and executive function deficits in DM patients. However, little is known how cerebral cortical circuitry changes in DM...
January 10, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29331263/glial-scars-are-permeable-to-the-neurotoxic-environment-of-chronic-stroke-infarcts
#4
Jacob C Zbesko, Thuy-Vi V Nguyen, Tao Yang, Jennifer Beischel Frye, Omar Hussain, Megan Hayes, Amanda Chung, W Anthony Day, Kristina Stepanovic, Maj Krumberger, Justine Mona, Frank M Longo, Kristian P Doyle
Following stroke, the damaged tissue undergoes liquefactive necrosis, a stage of infarct resolution that lasts for months, although the exact length of time is currently unknown. One method of repair involves reactive astrocytes and microglia forming a glial scar to compartmentalize the area of liquefactive necrosis from the rest of the brain. The formation of the glial scar is a critical component of the healing response to stroke, as well as other central nervous system (CNS) injuries. The goal of this study was to evaluate the toxicity of the extracellular fluid present in areas of liquefactive necrosis and determine how effectively it is segregated from the remainder of the brain...
January 10, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29330040/yod1-attenuates-neurogenic-proteotoxicity-through-its-deubiquitinating-activity
#5
Kunikazu Tanji, Fumiaki Mori, Yasuo Miki, Jun Utsumi, Hidenao Sasaki, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi
Ubiquitination, a fundamental post-translational modification of intracellular proteins, is enzymatically reversed by deubiquitinase enzymes (deubiquitinases). >90 deubiquitinases have been identified. One of these enzymes, YOD1, possesses deubiquitinase activity and is similar to ovarian tumor domain-containing protein 1, which is associated with regulation of the endoplasmic reticulum (ER)-associated degradation pathway. Indeed, YOD1 is reported to be involved in the ER stress response induced by mislocalization of unfolded proteins in mammalian cells...
January 10, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29330041/acute-epileptiform-activity-induced-by-gabazine-involves-proteasomal-rather-than-lysosomal-degradation-of-kca2-2-channels
#6
Steffen Müller, Xiati Guli, Judith Hey, Anne Einsle, Daniela Pfanz, Victor Sudmann, Timo Kirschstein, Rüdiger Köhling
Voltage-independent, Ca2+-activated K+ channels (KCa2.2, previously named SK2) are typically activated during a train of action potentials, and hence, are powerful regulators of cellular excitability by generating an afterhyperpolarizing potential (AHP) following prolonged excitation. In the acute in vitro epilepsy model induced in hippocampal brain slice preparations by exposure to the GABAA receptor blocker gabazine (GZ), the AHP was previously shown to be significantly decreased. Here, we asked the question whether KCa2...
January 9, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29325869/microglial-activation-and-the-nitric-oxide-cgmp-pkg-pathway-underlie-enhanced-neuronal-vulnerability-to-mitochondrial-dysfunction-in-experimental-multiple-sclerosis
#7
Andrea Mancini, Michela Tantucci, Petra Mazzocchetti, Antonio de Iure, Valentina Durante, Lara Macchioni, Carmela Giampà, Alessandra Alvino, Lorenzo Gaetani, Cinzia Costa, Alessandro Tozzi, Paolo Calabresi, Massimiliano Di Filippo
During multiple sclerosis (MS), a close link has been demonstrated to occur between inflammation and neuro-axonal degeneration, leading to the hypothesis that immune mechanisms may promote neurodegeneration, leading to irreversible disease progression. Energy deficits and inflammation-driven mitochondrial dysfunction seem to be involved in this process. In this work we investigated, by the use of striatal electrophysiological field-potential recordings, if the inflammatory process associated with experimental autoimmune encephalomyelitis (EAE) is able to influence neuronal vulnerability to the blockade of mitochondrial complex IV, a crucial component for mitochondrial activity responsible of about 90% of total cellular oxygen consumption...
January 8, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29307661/spatio-temporal-dynamics-of-cortical-drive-to-human-subthalamic-nucleus-neurons-in-parkinson-s-disease
#8
Andrew Sharott, Alessandro Gulberti, Wolfgang Hamel, Johannes A Köppen, Alexander Münchau, Carsten Buhmann, Monika Pötter-Nerger, Manfred Westphal, Christian Gerloff, Christian K E Moll, Andreas K Engel
Pathological synchronisation of beta frequency (12-35Hz) oscillations between the subthalamic nucleus (STN) and cerebral cortex is thought to contribute to motor impairment in Parkinson's disease (PD). For this cortico-subthalamic oscillatory drive to be mechanistically important, it must influence the firing of STN neurons and, consequently, their downstream targets. Here, we examined the dynamics of synchronisation between STN LFPs and units with multiple cortical areas, measured using frontal ECoG, midline EEG and lateral EEG, during rest and movement...
January 4, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29278738/slowing-disease-progression-in-the-sod1-mouse-model-of-als-by-blocking-neuregulin-induced-microglial-activation
#9
Jianguo Liu, Elise Allender, Jiajing Wang, Eleanor H Simpson, Jeffrey A Loeb, Fei Song
There are no effective treatments to slow disease progression in ALS. We previously reported that neuregulin (NRG) receptors are constitutively activated on microglia in the ventral horns in both ALS patients and SOD1 mice and in the corticospinal tracts of ALS patients, and that NRG receptor activation occurs prior to significant clinical disease onset in SOD1 mice. Here, we hypothesize that blocking NRG signaling on microglia would slow disease progression in SOD1 mice using a targeted NRG antagonist (HBD-S-H4)...
December 23, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29277556/microrna-16-targets-mrna-involved-in-neurite-extension-and-branching-in-hippocampal-neurons-during-presymptomatic-prion-disease
#10
Kristyn Burak, Lise Lamoureux, Amrit Boese, Anna Majer, Reuben Saba, Yulian Niu, Kathy Frost, Stephanie A Booth
The mechanisms that lead to neuronal death in neurodegenerative diseases are poorly understood. Prion diseases, like many more common disorders such as Alzheimer's and Parkinson's diseases, are characterized by the progressive accumulation of misfolded disease-specific proteins. The earliest changes observed in brain tissue include a reduction in synaptic number and retraction of dendritic spines, followed by reduced length and branching of neurites. These pathologies are observable during presymptomatic stages of disease and are accompanied by altered expression of transcripts that include miRNAs...
December 22, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29274743/ankrd11-associated-with-intellectual-disability-and-autism-regulates-dendrite-differentiation-via-the-bdnf-trkb-signaling-pathway
#11
Minhan Ka, Woo-Yang Kim
Haploinsufficiency of ANKRD11 due to deletion or truncation mutations causes KBG syndrome, a rare genetic disorder characterized by intellectual disability, autism spectrum disorder, and craniofacial abnormalities. However, little is known about the neurobiological role of ANKRD11 during brain development. Here we show that ANKRD11 regulates pyramidal neuron migration and dendritic differentiation in the developing moue cerebral cortex. Using an in utero manipulation approach, we found that Ankrd11 knockdown delayed radial migration of cortical neurons...
December 21, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29274742/effect-of-early-embryonic-deletion-of-huntingtin-from-pyramidal-neurons-on-the-development-and-long-term-survival-of-neurons-in-cerebral-cortex-and-striatum
#12
I Dragatsis, P Dietrich, H Ren, Y P Deng, N Del Mar, H B Wang, I M Johnson, K R Jones, A Reiner
We evaluated the impact of early embryonic deletion of huntingtin (htt) from pyramidal neurons on cortical development, cortical neuron survival and motor behavior, using a cre-loxP strategy to inactivate the mouse htt gene (Hdh) in emx1-expressing cell lineages. Western blot confirmed substantial htt reduction in cerebral cortex of these Emx-httKO mice, with residual cortical htt in all likelihood restricted to cortical interneurons of the subpallial lineage and/or vascular endothelial cells. Despite the loss of htt early in development, cortical lamination was normal, as revealed by layer-specific markers...
December 21, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29274741/a-novel-therapeutic-approach-for-treatment-of-catamenial-epilepsy
#13
Suchitra Joshi, Huayu Sun, Karthik Rajasekaran, John Williamson, Edward Perez-Reyes, Jaideep Kapur
Many women with epilepsy experience perimenstrual seizure exacerbation, referred to as catamenial epilepsy. There is no effective treatment for this condition, proposed to result from withdrawal of neurosteroid-mediated effects of progesterone. A double-blind, multicenter, phase III, clinical trial of catamenial epilepsy has failed to find a beneficial effect of progesterone. The neurosteroid-mediated effects of progesterone have been extensively studied in relation to catamenial epilepsy; however, the effects mediated by progesterone receptor activation have been overlooked...
December 21, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29274432/a-mouse-model-of-depdc5-related-epilepsy-neuronal-loss-of-depdc5-causes-dysplastic-and-ectopic-neurons-increased-mtor-signaling-and-seizure-susceptibility
#14
Christopher J Yuskaitis, Brandon M Jones, Rachel L Wolfson, Chloe E Super, Sameer C Dhamne, Alexander Rotenberg, David M Sabatini, Mustafa Sahin, Annapurna Poduri
DEPDC5 is a newly identified epilepsy-related gene implicated in focal epilepsy, brain malformations, and Sudden Unexplained Death in Epilepsy (SUDEP). In vitro, DEPDC5 negatively regulates amino acid sensing by the mTOR complex 1 (mTORC1) pathway, but the role of DEPDC5 in neurodevelopment and epilepsy has not been described. No animal model of DEPDC5-related epilepsy has recapitulated the neurological phenotypes seen in patients, and germline knockout rodent models are embryonic lethal. Here, we establish a neuron-specific Depdc5 conditional knockout mouse by cre-recombination under the Synapsin1 promotor...
December 20, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29274431/trajectory-of-inflammatory-and-microglial-activation-markers-in-the-postnatal-rabbit-brain-following-intrauterine-endotoxin-exposure
#15
Zhi Zhang, Amar Jyoti, Bindu Balakrishnan, Monica Williams, Sarabdeep Singh, Diane C Chugani, Sujatha Kannan
BACKGROUND: Maternal infection is a risk factor for periventricular leukomalacia and cerebral palsy (CP) in neonates. We have previously demonstrated hypomyelination and motor deficits in newborn rabbits, as seen in patients with cerebral palsy, following maternal intrauterine endotoxin administration. This was associated with increased microglial activation, primarily involving the periventricular region (PVR). In this study we hypothesized that maternal intrauterine inflammation leads to a pro-inflammatory environment in the PVR that is associated with microglial activation in the first 2 postnatal weeks...
December 20, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29274430/divergent-brain-changes-in-two-audiogenic-rat-strains-a-voxel-based-morphometry-and-diffusion-tensor-imaging-comparison-of-the-genetically-epilepsy-prone-rat-gepr-3-and-the-wistar-audiogenic-rat-war
#16
Yichien Lee, Olga C Rodriguez, Chris Albanese, Victor Rodrigues Santos, José Antônio Cortes de Oliveira, Ana Luiza Ferreira Donatti, Artur Fernandes, Norberto Garcia-Cairasco, Prosper N'Gouemo, Patrick A Forcelli
Acoustically evoked seizures (e.g., audiogenic seizures or AGS) are common in models of inherited epilepsy and occur in a variety of species including rat, mouse, and hamster. Two models that have been particularly well studied are the genetically epilepsy prone rat (GEPR-3) and the Wistar Audiogenic Rat (WAR) strains. Acute and repeated AGS, as well as comorbid conditions, displays a close phenotypic overlap in these models. Whether these similarities arise from convergent or divergent structural changes in the brain remains unknown...
December 20, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29274429/retinoic-acid-synthesis-by-ng2-expressing-cells-promotes-a-permissive-environment-for-axonal-outgrowth
#17
Maria B Goncalves, Yue Wu, Diogo Trigo, Earl Clarke, Tony Malmqvist, John Grist, Carl Hobbs, Thomas Carlstedt, Jonathan P T Corcoran
Stimulation of retinoic acid (RA) mediated signalling pathways following neural injury leads to regeneration in the adult nervous system and numerous studies have shown that the specific activation of the retinoic acid receptor β (RARβ) is required for this process. Here we identify a novel mechanism by which neuronal RARβ activation results in the endogenous synthesis of RA which is released in association with exosomes and acts as a positive cue to axonal/neurite outgrowth. Using an established rodent model of RARβ induced axonal regeneration, we show that neuronal RARβ activation upregulates the enzymes involved in RA synthesis in a cell specific manner; alcohol dehydrogenase7 (ADH7) in neurons and aldehyde dehydrogenase 2 (Raldh2) in NG2 expressing cells (NG2+ cells)...
December 20, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29272738/monomeric-amyloid-%C3%AE-reduced-amyloid-%C3%AE-oligomer-induced-synapse-damage-in-neuronal-cultures
#18
Clive Bate, Alun Williams
Alzheimer's disease is a progressive neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) in the brain. Aβ oligomers are believed to cause synapse damage resulting in the memory deficits that are characteristic of this disease. Since the loss of synaptic proteins in the brain correlates closely with the degree of dementia in Alzheimer's disease, the process of Aβ-induced synapse damage was investigated in cultured neurons by measuring the loss of synaptic proteins. Soluble Aβ oligomers, derived from Alzheimer's-affected brains, caused the loss of cysteine string protein and synaptophysin from neurons...
December 19, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29248540/sodium-butyrate-triggers-a-functional-elongation-of-microglial-process-via-akt-small-rhogtpase-activation-and-hdacs-inhibition
#19
Peng Wang, Yaru Zhang, Yu Gong, Rongrong Yang, Zhuo Chen, Wenfeng Hu, Yue Wu, Minhui Gao, Xing Xu, Yibin Qin, Chao Huang
Microglia, a type of immune cell in the brain, are in a ramified status with branched processes in normal conditions. Upon pathological stimulation, microglia retract their processes and become activated. Searching methods to make the activated microglia return to ramified status would help cope with injuries induced by neuroinflammation. Here, we investigated the influence of sodium butyrate (SB), a sodium salt form of butyrate produced by fermentation of dietary fibers in the gut on microglial process. Results showed that SB induced reversible elongations of microglial process in both normal and inflammatory conditions, and these elongations were accompanied with significant changes in markers reflecting the pro-inflammatory and anti-inflammatory status of microglia...
December 14, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29246724/toxic-properties-of-microsome-associated-alpha-synuclein-species-in-mouse-primary-neurons
#20
Emanuela Colla, Giulia Panattoni, Alessio Ricci, Caterina Rizzi, Lucia Rota, Nicola Carucci, Verdiana Valvano, Francesco Gobbo, Simona Capsoni, Michael K Lee, Antonino Cattaneo
α-synuclein (αS) is a small protein that self-aggregates into α-helical oligomer species and subsequently into larger insoluble amyloid fibrils that accumulate in intraneuronal inclusions during the development of Parkinson's disease. Toxicity of αS oligomers and fibrils has been long debated and more recent data are suggesting that both species can induce neurodegeneration. However while most of these data are based on differences in structure between oligomer and aggregates, often preassembled in vitro, the in vivo situation might be more complex and subcellular locations where αS species accumulate, rather than their conformation, might contribute to enhanced toxicity...
December 12, 2017: Neurobiology of Disease
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