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Neurobiology of Disease

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https://www.readbyqxmd.com/read/28720484/long-term-enzyme-replacement-therapy-improves-neurocognitive-functioning-and-hippocampal-synaptic-plasticity-in-immune-tolerant-alpha-mannosidosis-mice
#1
Stijn Stroobants, Markus Damme, Ann Van der Jeugd, Ben Vermaercke, Claes Andersson, Jens Fogh, Paul Saftig, Judith Blanz, Rudi D'Hooge
Alpha-mannosidosis is a glycoproteinosis caused by deficiency of lysosomal acid alpha-mannosidase (LAMAN), which markedly affects neurons of the central nervous system (CNS), and causes pathognomonic intellectual dysfunction in the clinical condition. Cognitive improvement consequently remains a major therapeutic objective in research on this devastating genetic error. Immune-tolerant LAMAN knockout mice were developed to evaluate the effects of enzyme replacement therapy (ERT) by prolonged administration of recombinant human enzyme...
July 15, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28711409/nortriptyline-inhibits-aggregation-and-neurotoxicity-of-alpha-synuclein-by-enhancing-reconfiguration-of-the-monomeric-form
#2
Timothy J Collier, Kinshuk R Srivastava, Craig Justman, Tom Grammatopoulous, Birgit Hutter-Paier, Manuela Prokesch, Daniel Havas, Jean-Christophe Rochet, Fang Liu, Kevin Jock, Patrícia de Oliveira, Georgia L Stirtz, Ulf Dettmer, Caryl E Sortwell, Mel B Feany, Peter Lansbury, Lisa Lapidus, Katrina L Paumier
The pathology of Parkinson's disease and other synucleinopathies is characterized by the formation of intracellular inclusions comprised primarily of misfolded, fibrillar α-synuclein (α-syn). One strategy to slow disease progression is to prevent the misfolding and aggregation of its native monomeric form. Here we present findings that support the contention that the tricyclic antidepressant compound nortriptyline (NOR) has disease-modifying potential for synucleinopathies. Findings from in vitro aggregation and kinetics assays support the view that NOR inhibits aggregation of α-syn by directly binding to the soluble, monomeric form, and by enhancing reconfiguration of the monomer, inhibits formation of toxic conformations of the protein...
July 12, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28709994/metabolic-correction-by-pyruvate-halts-acquired-epilepsy-in-multiple-rodent-models
#3
I Popova, A Malkov, A I Ivanov, E Samokhina, S Buldakova, O Gubkina, A Osypov, R S Muhammadiev, T Zilberter, M Molchanov, S Paskevich, M Zilberter, Y Zilberter
Metabolic intervention strategy of epilepsy treatment has been gaining broader attention due to accumulated evidence that hypometabolism, manifested in humans as reduced brain glucose consumption, is a principal factor in acquired epilepsy. Therefore, targeting deficient energy metabolism may be an effective approach for treating epilepsy. To confront this pathology we utilized pyruvate, which besides being an anaplerotic mitochondrial fuel possesses a unique set of neuroprotective properties as it: (i) is a potent reactive oxygen species scavenger; (ii) abates overactivation of Poly [ADP-ribose] polymerase 1 (PARP-1); (iii) facilitates glutamate efflux from the brain; (iv) augments brain glycogen stores; (v) is anti-inflammatory; (vi) prevents neuronal hyperexcitability; and (vii) normalizes the cytosolic redox state...
July 12, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28709993/intracellular-calcium-release-through-ip3r-or-ryr-contributes-to-secondary-axonal-degeneration
#4
Ben C Orem, Nicolas Pelisch, Joshua Williams, Jacqueline M Nally, David P Stirling
Severed CNS axons often retract or dieback away from the injury site and fail to regenerate. The precise mechanisms underlying acute axonal dieback and secondary axonal degeneration remain poorly understood. Here we investigate the role of Ca(2+) store mediated intra-axonal Ca(2+) release in acute axonal dieback and secondary axonal degeneration. To differentiate between primary (directly transected) and "bystander" axonal injury (axons spared by the initial injury but then succumb to secondary degeneration) in real-time we use our previously published highly focal laser-induced spinal cord injury (LiSCI) ex vivo model...
July 12, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28709992/time-dependent-evolution-of-seizures-in-a-model-of-mesial-temporal-lobe-epilepsy
#5
Charles Behr, Maxime Lévesque, Thomas Stroh, Massimo Avoli
Low-voltage fast (LVF) and hypersynchronous (HYP) - onset seizures occur in the EEG obtained with depth electrodes from mesial temporal lobe epilepsy (MTLE) patients and animal models. In epileptic rats analyzed up to approximately two weeks after pilocarpine-induced status epilepticus (SE), these patterns are associated with specific high-frequency oscillation (HFO) content: ripples (80-200Hz) or fast-ripples (250-500Hz) predominate in LVF or HYP seizures, respectively. To establish whether these features change over the course of the disease, we recorded the EEG from the hippocampal CA3 subfield, subiculum, entorhinal cortex and dentate gyrus in two groups of pilocarpine-treated rats: the "early stage group" (n=8) was analyzed from day 3 to 20 post-SE while the "late stage group" (n=7) was studied from day 27 to 53 post-SE...
July 12, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28709995/the-contribution-of-biophysical-and-structural-studies-of-protein-self-assembly-to-the-design-of-therapeutic-strategies-for-amyloid-diseases
#6
Nunilo Cremades, Christopher M Dobson
Many neurodegenerative disorders, including Alzheimer's, Parkinson's and the prion diseases, are characterized by a conformational conversion of normally soluble proteins or peptides into pathological species, by a process of misfolding and self-assembly that leads ultimately to the formation of amyloid fibrils. Recent studies support the idea that multiple intermediate species with a wide variety of degrees of neuronal toxicity are generated during such processes. The development of a high level of knowledge of the nature and structure of the pathogenic amyloid species would significantly enhance efforts to underline the molecular origins of these disorders and also to develop both accurate diagnoses and effective therapeutic interventions for these types of conditions...
July 11, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28690143/the-brain-penetrant-5-ht7-receptor-agonist-lp-211-reduces-the-sensory-and-affective-components-of-neuropathic-pain
#7
Mirko Santello, Alberto Bisco, Natalie Elisabeth Nevian, Enza Lacivita, Marcello Leopoldo, Thomas Nevian
Neuropathic pain is a debilitating pathological condition of high clinical relevance. Changes in neuronal excitability in the anterior cingulate cortex (ACC) play a central role in the negative emotional and affective aspects of chronic pain. We evaluated the effects of LP-211, a new serotonin-receptor-type-7 (5-HT7R) agonist that crosses the blood-brain barrier, on ACC neurons in a mouse model of neuropathic pain. LP-211 reduced synaptic integration in layer 5 pyramidal neurons, which was enhanced in neuropathic pain due to a dysfunction of dendritic hyperpolarization-activated-and-cyclic-nucleotide-regulated (HCN) channels...
July 6, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28688853/gpr37l1-modulates-seizure-susceptibility-evidence-from-mouse-studies-and-analyses-of-a-human-gpr37l1-variant
#8
Michelle M Giddens, Jennifer C Wong, Jason P Schroeder, Emily G Farrow, Brilee M Smith, Sharon Owino, Sarah E Soden, Rebecca C Meyer, Carol Saunders, J B LePichon, David Weinshenker, Andrew Escayg, Randy A Hall
Progressive myoclonus epilepsies (PMEs) are disorders characterized by myoclonic and generalized seizures with progressive neurological deterioration. While several genetic causes for PMEs have been identified, the underlying causes remain unknown for a substantial portion of cases. Here we describe several affected individuals from a large, consanguineous family presenting with a novel PME in which symptoms begin in adolescence and result in death by early adulthood. Whole exome analyses revealed that affected individuals have a homozygous variant in GPR37L1 (c...
July 6, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28688852/cdkl5-controls-postsynaptic-localization-of-glun2b-containing-nmda-receptors-in-the-hippocampus-and-regulates-seizure-susceptibility
#9
Kosuke Okuda, Shizuka Kobayashi, Masahiro Fukaya, Aya Watanabe, Takuto Murakami, Mai Hagiwara, Tempei Sato, Hiroe Ueno, Narumi Ogonuki, Sayaka Komano-Inoue, Hiroyuki Manabe, Masahiro Yamaguchi, Atsuo Ogura, Hiroshi Asahara, Hiroyuki Sakagami, Masashi Mizuguchi, Toshiya Manabe, Teruyuki Tanaka
Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders accompanied by intractable epilepsies, i.e. West syndrome or atypical Rett syndrome. Here we report generation of the Cdkl5 knockout mouse and show that CDKL5 controls postsynaptic localization of GluN2B-containing N-methyl-d-aspartate (NMDA) receptors in the hippocampus and regulates seizure susceptibility. Cdkl5 -/Y mice showed normal sensitivity to kainic acid; however, they displayed significant hyperexcitability to NMDA...
July 6, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28688851/characterization-of-the-dominant-inheritance-mechanism-of-episodic-ataxia-type-2
#10
Kevin Dorgans, Julie Salvi, Federica Bertaso, Ludivine Bernard, Philippe Lory, Frederic Doussau, Alexandre Mezghrani
Episodic Ataxia type 2 (EA2) is an autosomal dominant neuronal disorder linked to mutations in the Cav2.1 subunit of P/Q-type calcium channels. In vitro studies have established that EA2 mutations induce loss of channel activity and that EA2 mutants can exert a dominant negative effect, suppressing normal Cav2.1 activity through protein misfolding and trafficking defects. To date, the role of this mechanism in the disease pathogenesis is unknown because no animal model exists. To address this issue, we have generated a mouse bearing the R1497X nonsense mutation in Cav2...
July 5, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28687442/increased-bace1-activity-inhibits-peripheral-nerve-regeneration-after-injury
#11
Carolyn Tallon, Edward Rockenstein, Eliezer Masliah, Mohamed H Farah
Axons of the peripheral nervous system possess the capacity to regenerate following injury. Previously, we showed that genetically knocking out Beta-Site APP-Cleaving Enzyme 1 (BACE1) leads to increased nerve regeneration. Two cellular components, macrophages and neurons, contribute to enhanced nerve regeneration in BACE1 knockout mice. Here, we utilized a transgenic mouse model that overexpresses BACE1 in its neurons to investigate whether neuronal BACE1 has an inverse effect on regeneration following nerve injury...
July 5, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28684271/ablating-erbb4-in-pv-neurons-attenuates-synaptic-and-cognitive-deficits-in-an-animal-model-of-alzheimer-s-disease
#12
Heng Zhang, Ling Zhang, Dongming Zhou, Xiao He, Dongpi Wang, Hongyu Pan, Xiaoqin Zhang, Yufei Mei, Qi Qian, Tingting Zheng, Frank E Jones, Binggui Sun
Accumulation of amyloid β (Aβ) induces neuronal, synaptic, and cognitive deficits in patients and animal models of Alzheimer's disease (AD). The underlying mechanisms, however, remain to be fully elucidated. In the present study, we found that Aβ interacted with ErbB4, a member of the receptor tyrosine kinase family and mainly expressed in GABAergic interneurons. Deleting ErbB4 in parvalbumin-expressing neurons (PV neurons) significantly attenuated oligomeric Aβ-induced suppression of long term potentiation (LTP)...
July 4, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28673740/forebrain-knock-out-of-torsina-reduces-striatal-free-water-and-impairs-whole-brain-functional-connectivity-in-a-symptomatic-mouse-model-of-dyt1-dystonia
#13
Jesse C DeSimone, Samuel S Pappas, Marcelo Febo, Roxana G Burciu, Priyank Shukla, Luis M Colon-Perez, William T Dauer, David E Vaillancourt
Multiple lines of evidence implicate striatal dysfunction in the pathogenesis of dystonia, including in DYT1, a common inherited form of the disease. The impact of striatal dysfunction on connected motor circuits and their interaction with other brain regions is poorly understood. Conditional knock-out (cKO) of the DYT1 protein torsinA from forebrain cholinergic and GABAergic neurons creates a symptomatic model that recapitulates many characteristics of DYT1 dystonia, including the developmental onset of overt twisting movements that are responsive to antimuscarinic drugs...
July 1, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28673739/sirtuin-3-rescues-neurons-through-the-stabilisation-of-mitochondrial-biogenetics-in-the-virally-expressing-mutant-%C3%AE-synuclein-rat-model-of-parkinsonism
#14
Jacqueline A Gleave, Lindsay R Arathoon, Dennison Trinh, Kristin E Lizal, Nicolas Giguère, James H M Barber, Zainab Najarali, M Hassan Khan, Sherri L Thiele, Mahin S Semmen, James B Koprich, Jonathan M Brotchie, James H Eubanks, Louis-Eric Trudeau, Joanne E Nash
Parkinson's disease (PD) is a neurodegenerative movement disorder, which affects approximately 1-2% of the population over 60years of age. Current treatments for PD are symptomatic, and the pathology of the disease continues to progresses over time until palliative care is required. Mitochondria are key players in the pathology of PD. Genetic and post mortem studies have shown a large number of mitochondrial abnormalities in the substantia nigra pars compacta (SNc) of the parkinsonian brain. Furthermore, physiologically, mitochondria of nigral neurons are constantly under unusually high levels of metabolic stress because of the excitatory properties and architecture of these neurons...
July 1, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28663119/minimal-traumatic-brain-injury-causes-persistent-changes-in-dna-methylation-at-bdnf-gene-promoters-in-rat-amygdala-a-possible-role-in-anxiety-like-behaviors
#15
Sneha Sagarkar, Tanmayi Bhamburkar, Gajanan Shelkar, Amit Choudhary, Dadasaheb M Kokare, Amul J Sakharkar
Minimal traumatic brain injury (MTBI) often transforms into chronic neuropsychiatric conditions including anxiety, the underlying mechanisms of which are largely unknown. In the present study, we employed the closed-head injury paradigm to induce MTBI in rats and examined whether DNA methylation can explain long-term changes in the expression of the brain-derived neurotrophic factor (BDNF) in the amygdala as well as trauma-induced anxiety-like behaviors. The MTBI caused anxiety-like behaviors and altered the expression of DNA methyltransferase (DNMT) isoforms (DNMT1, DNMT3a, and DNMT3b) and factors involved in DNA demethylation such as the growth arrest and DNA damage 45 (GADD45a and GADD45b)...
June 27, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28651891/neuroanatomical-alterations-and-synaptic-plasticity-impairment-in-the-perirhinal-cortex-of-the-ts65dn-mouse-model-of-down-syndrome
#16
Vincenzo Roncacé, Costanza Burattini, Fiorenza Stagni, Sandra Guidi, Andrea Giacomini, Marco Emili, Giorgio Aicardi, Renata Bartesaghi
Down syndrome (DS), a genetic condition due to triplication of Chromosome 21, is characterized by numerous neurodevelopmental alterations and intellectual disability. Individuals with DS and DS mouse models are impaired in several memory domains, including hippocampus-dependent declarative (spatial, in rodents) memory and visual recognition memory, a form of memory in which the perirhinal cortex (PRC) plays a fundamental role. The anatomo-functional substrates of hippocampus-dependent memory impairment have been largely elucidated in the Ts65Dn mouse model of DS...
June 23, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28648742/polo-like-kinase-2-modulates-%C3%AE-synuclein-protein-levels-by-regulating-its-mrna-production
#17
Rikke H Kofoed, Jin Zheng, Nelson Ferreira, Søren Lykke-Andersen, Mauro Salvi, Cristine Betzer, Lasse Reimer, Torben Heick Jensen, Karina Fog, Poul H Jensen
Variations in the α-synuclein-encoding SNCA gene represent the greatest genetic risk factor for Parkinson's disease (PD), and duplications/triplications of SNCA cause autosomal dominant familial PD. These facts closely link brain levels of α-synuclein with the risk of PD, and make lowering α-synuclein levels a therapeutic strategy for the treatment of PD and related synucleinopathies. In this paper, we corroborate previous findings on the ability of overexpressed Polo-like kinase 2 (PLK-2) to decrease cellular α-synuclein, but demonstrate that the process is independent of PLK-2 phosphorylating S129 in α-synuclein because a similar reduction is achieved with the non-phosphorable S129A mutant α-synuclein...
June 23, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28647557/kcc3-loss-of-function-contributes-to-andermann-syndrome-by-inducing-activity-dependent-neuromuscular-junction-defects
#18
Melissa Bowerman, Céline Salsac, Véronique Bernard, Claire Soulard, Annie Dionne, Emmanuelle Coque, Salim Benlefki, Pascale Hince, Patrick A Dion, Gillian Butler-Browne, William Camu, Jean-Pierre Bouchard, Eric Delpire, Guy A Rouleau, Cédric Raoul, Frédérique Scamps
Loss-of-function mutations in the potassium-chloride cotransporter KCC3 lead to Andermann syndrome, a severe sensorimotor neuropathy characterized by areflexia, amyotrophy and locomotor abnormalities. The molecular events responsible for axonal loss remain poorly understood. Here, we establish that global or neuron-specific KCC3 loss-of-function in mice leads to early neuromuscular junction (NMJ) abnormalities and muscular atrophy that are consistent with the pre-synaptic neurotransmission defects observed in patients...
June 21, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28647556/synapsin-i-phosphorylation-is-dysregulated-by-beta-amyloid-oligomers-and-restored-by-valproic-acid
#19
Jade Marsh, Saifuddien Haji Bagol, Robin S B Williams, George Dickson, Pavlos Alifragis
Alzheimer's disease is the most prevalent form of dementia in the elderly but the precise causal mechanisms are still not fully understood. Growing evidence supports a significant role for Aβ42 oligomers in the development and progression of Alzheimer's. For example, intracellular soluble Aβ oligomers are thought to contribute to the early synaptic dysfunction associated with Alzheimer's disease, but the molecular mechanisms underlying this effect are still unclear. Here, we identify a novel mechanism that contributes to our understanding of the reported synaptic dysfunction...
June 21, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28647555/normalizing-the-gene-dosage-of-dyrk1a-in-a-mouse-model-of-down-syndrome-rescues-several-alzheimer-s-disease-phenotypes
#20
Susana García-Cerro, Noemí Rueda, Verónica Vidal, Sara Lantigua, Carmen Martínez-Cué
The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology...
June 21, 2017: Neurobiology of Disease
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