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Neurobiology of Disease

Jewel L Podratz, Han Lee, Patrizia Knorr, Stephanie Koehler, Steven Forsythe, Kelsey Lambrecht, Suzette Arias, Kiley Schmidt, Gabrielle Steinhoff, Georgiy Yudintsev, Amy Yang, Eugenia Trushina, Anthony Windebank
Cisplatin is an effective chemotherapy drug that induces peripheral neuropathy in cancer patients. In rodent dorsal root ganglion neurons, cisplatin binds nuclear and mitochondrial DNA (mtDNA) inducing DNA damage and apoptosis. Platinum-mtDNA adducts inhibit mtDNA replication and transcription leading to mitochondrial degradation. Cisplatin also induces climbing deficiencies associated with neuronal apoptosis in adult Drosophila melanogaster. Here we used Drosophila larvae that express green fluorescent protein in the mitochondria of motor neurons to observe the effects of cisplatin on mitochondrial dynamics and function...
October 17, 2016: Neurobiology of Disease
Marta Silva, José Tiago Costa-Pereira, Daniel Martins, Isaura Tavares
Diabetic neuropathy has a profound impact in the quality of life of patients who frequently complain of pain. The mechanisms underlying diabetic neuropathic pain (DNP) are no longer ascribed only to damage of peripheral nerves. The effects of diabetes at the central nervous system are currently considered causes of DPN. Management of DNP may be achieved by antidepressants that act on serotonin (5-HT) uptake, namely specific serotonin reuptake inhibitors. The rostroventromedial medulla (RVM) is a key pain control center involved in descending pain modulation at the spinal cord through local release of 5-HT and plays a peculiar role in the balance of bidirectional control (i...
October 4, 2016: Neurobiology of Disease
Jeremy S Francis, Ireneusz Wojtas, Vladimir Markov, Steven J Gray, Thomas J McCown, R Jude Samulski, Larissa T Bilaniuk, Dah-Jyuu Wang, Darryl C De Vivo, Christopher G Janson, Paola Leone
Breakdown of neuro-glial N-acetyl-aspartate (NAA) metabolism results in the failure of developmental myelination, manifest in the congenital pediatric leukodystrophy Canavan disease caused by mutations to the sole NAA catabolizing enzyme aspartoacylase. Canavan disease is a major point of focus for efforts to define NAA function, with available evidence suggesting NAA serves as an acetyl donor for fatty acid synthesis during myelination. Elevated NAA is a diagnostic hallmark of Canavan disease, which contrasts with a broad spectrum of alternative neurodegenerative contexts in which levels of NAA are inversely proportional to pathological progression...
October 4, 2016: Neurobiology of Disease
Carlo Perego, Stefano Fumagalli, Elisa R Zanier, Erika Carlino, Nicolò Panini, Eugenio Erba, Maria-Grazia De Simoni
Resident microglia and recruited macrophages are major contributors to the post-ischemic inflammatory response. Initially considered functionally homogeneous populations, data now suggest distinct but still controversial roles after brain injury. Using a model of conditional monocyte/macrophage depletion we studied the contribution of these myeloid cells to brain lesion progression after ischemia, and their influence on the ischemic inflammatory environment. Male CD11b-DTR transgenic mice, expressing the human diphtheria toxin receptor under the control of the CD11b promoter, were treated with diphtheria toxin to induce monocyte/macrophage depletion...
September 30, 2016: Neurobiology of Disease
Masao Horie, Kazuyuki Mekada, Hiromi Sano, Yoshiaki Kikkawa, Satomi Chiken, Takuro Someya, Keisuke Saito, M Ibrahim Hossain, Masaaki Nameta, Kuniya Abe, Kenji Sakimura, Katsuhiko Ono, Atsushi Nambu, Atsushi Yoshiki, Hirohide Takebayashi
We identified a novel spontaneous mutant mouse showing motor symptoms that are similar to those of the dystonia musculorum (dt) mouse. The observations suggested that the mutant mice inherited the mild dt phenotype as an autosomal recessive trait. Linkage analysis showed that the causative gene was located near D1Mit373 and D1Mit410 microsatellite markers on chromosome 1, which are close to the dystonin (Dst) gene locus. To investigate whether Dst is the causative gene of the novel mutant phenotype, we crossed the mutant with Dst gene trap (Dst(Gt)) mice...
September 28, 2016: Neurobiology of Disease
Aurore Nkiliza, Eugénie Mutez, Clémence Simonin, Frédéric Leprêtre, Aurélie Duflot, Martin Figeac, Céline Villenet, Pierre Semaille, Thomas Comptdaer, Alexandre Genet, Bernard Sablonnière, David Devos, Luc Defebvre, Alain Destée, Marie-Christine Chartier-Harlin
CAG triplet expansions in Ataxin-2 gene (ATXN2) cause spinocerebellar ataxia type 2 and have a role that remains to be clarified in Parkinson's disease (PD). To study the molecular events associated with these expansions, we sequenced them and analyzed the transcriptome from blood cells of controls and three patient groups diagnosed with spinocerebellar ataxia type 2 (herein referred to as SCA2c) or PD with or without ATXN2 triplet expansions (named SCA2p). The transcriptome profiles of these 40 patients revealed three main observations: i) a specific pattern of pathways related to cellular contacts, proliferation and differentiation associated with SCA2p group, ii) similarities between the SCA2p and sporadic PD groups in genes and pathways known to be altered in PD such as Wnt, Ephrin and Leukocyte extravasation signaling iii) RNA metabolism disturbances with "RNA-binding" and "poly(A) RNA-binding" as a common feature in all groups...
September 20, 2016: Neurobiology of Disease
N M de Wit, J Vanmol, A Kamermans, Jja Hendriks, H E de Vries
The blood-brain barrier (BBB) is indispensable for the maintenance of brain homeostasis and proper neuronal functioning. Dysfunction of the BBB significantly contributes to the pathogenesis of neuroinflammatory and neurodegenerative diseases like stroke, multiple sclerosis (MS), and Alzheimer's disease (AD). The neuroinflammatory environment that characterizes these disorders propagates chronic impaired function of the BBB, processes that will be discussed in this review. Limiting dysfunction of the BBB may be an attractive target for treatment of neurological disorders...
September 20, 2016: Neurobiology of Disease
S Y Yau, C A Bostrom, J Chiu, C J Fontaine, S Sawchuk, A Meconi, R C Wortman, E Truesdell, A Truesdell, C Chiu, B N Hryciw, B D Eadie, M Ghilan, B R Christie
Fragile-X syndrome (FXS) is caused by the transcriptional repression of the Fmr1 gene resulting in loss of the Fragile-X mental retardation protein (FMRP). This leads to cognitive impairment in both male and female patients, however few studies have focused on the impact of FXS in females. Significant cognitive impairment has been reported in approximately 35% of women who exhibit a heterozygous Fmr1 gene mutation, however to date there is a paucity of information regarding the mechanistic underpinnings of these deficits...
September 19, 2016: Neurobiology of Disease
Jin Hwan Lee, Zheng Z Wei, Wenyuan Cao, Soonmi Won, Xiaohuan Gu, Megan Winter, Thomas A Dix, Ling Wei, Shan Ping Yu
Stroke is a leading threat to human life and health in the US and around the globe, while very few effective treatments are available for stroke patients. Preclinical and clinical studies have shown that therapeutic hypothermia (TH) is a potential treatment for stroke. Using novel neurotensin receptor 1 (NTR1) agonists, we have demonstrated pharmacologically induced hypothermia and protective effects against brain damages after ischemic stroke, hemorrhage stroke, and traumatic brain injury (TBI) in rodent models...
September 19, 2016: Neurobiology of Disease
Arezu Jahani-Asl, Cheng Cheng, Chi Zhang, Azad Bonni
Intellectual disability encompasses a large set of neurodevelopmental disorders of cognition that are more common in males than females. Although mutations in over 100 X-linked genes associated to intellectual disability have been identified, only a few X-linked intellectual disability proteins have been intensively studied. Hence, the molecular mechanisms underlying the majority of X-linked intellectual disability disorders remain poorly understood. A substantial fraction of X-linked intellectual disability genes encode nuclear proteins, suggesting that elucidating their functions in the regulation of transcription may provide novel insights into the pathogenesis of intellectual disability...
September 12, 2016: Neurobiology of Disease
Christine Altmann, Stefanie Hardt, Caroline Fischer, Juliana Heidler, Hee-Young Lim, Annett Häussler, Boris Albuquerque, Béla Zimmer, Christine Möser, Christian Behrends, Frank Koentgen, Ilka Wittig, Mirko H H Schmidt, Albrecht M Clement, Thomas Deller, Irmgard Tegeder
Peripheral or central nerve injury is a frequent cause of chronic pain and the mechanisms are not fully understood. Using newly generated transgenic mice we show that progranulin overexpression in sensory neurons attenuates neuropathic pain after sciatic nerve injury and accelerates nerve healing. A yeast-2-hybrid screen revealed putative interactions of progranulin with autophagy-related proteins, ATG12 and ATG4b. This was supported by colocalization and proteomic studies showing regulations of ATG13 and ATG4b and other members of the autophagy network, lysosomal proteins and proteins involved in endocytosis...
September 11, 2016: Neurobiology of Disease
Eduardo E Arteaga-Bracho, Maria Gulinello, Michael L Winchester, Nandini Pichamoorthy, Jenna R Petronglo, Alicia D Zambrano, Julio Inocencio, Chirstopher D De Jesus, Joseph O Louie, Solen Gokhan, Mark F Mehler, Aldrin E Molero
The mutation in huntingtin (mHtt) leads to a spectrum of impairments in the developing forebrain of Huntington's disease (HD) mouse models. Whether these developmental alterations are due to loss- or gain-of-function mechanisms and contribute to HD pathogenesis is unknown. We examined the role of selective loss of huntingtin (Htt) function during development on postnatal vulnerability to cell death. We employed mice expressing very low levels of Htt throughout embryonic life to postnatal day 21 (Hdh(d•hyp))...
September 10, 2016: Neurobiology of Disease
Richard P Hulse, Robert A R Drake, David O Bates, Lucy F Donaldson
Neuropathic pain results from neuroplasticity in nociceptive neuronal networks. Here we demonstrate that control of alternative pre-mRNA splicing, through the splice factor serine-arginine splice factor 1 (SRSF1), is integral to the processing of nociceptive information in the spinal cord. Neuropathic pain develops following a partial saphenous nerve ligation injury, at which time SRSF1 is activated in damaged myelinated primary afferent neurons, with minimal found in small diameter (IB4 positive) dorsal root ganglia neurons...
September 9, 2016: Neurobiology of Disease
Deniz Kirik, Erik Cederfjäll, Glenda Halliday, Åsa Petersén
Gene transfer is a promising drug delivery method of advanced therapeutic entities for Parkinson's disease. One advantage over conventional therapies, such as peripheral delivery of the dopamine pre-cursor l-DOPA, is site-specific expression of proteins with regenerative, disease-modifying and potentially neuroprotective capacity. Several clinical trials have been performed to test the capacity of glial-cell line derived neurotrophic factor and neurturin to rescue degenerating dopaminergic neurons in the substantia nigra and their axon terminals in the striatum by delivery of these neurotrophic factors either as purified protein or by means of viral vector mediated gene delivery to the brain...
September 8, 2016: Neurobiology of Disease
Konrad Juczewski, Helen von Richthofen, Claudia Bagni, Tansu Celikel, Gilberto Fisone, Patrik Krieger
Fragile X syndrome (FXS) is a common inherited form of intellectual disability caused by the absence or reduction of the fragile X mental retardation protein (FMRP) encoded by the FMR1 gene. In humans, one symptom of FXS is hypersensitivity to sensory stimuli, including touch. We used a mouse model of FXS (Fmr1 KO) to study sensory processing of tactile information conveyed via the whisker system. In vivo electrophysiological recordings in somatosensory barrel cortex showed layer-specific broadening of the receptive fields at the level of layer 2/3 but not layer 4, in response to whisker stimulation...
September 8, 2016: Neurobiology of Disease
Mariana Rinaldi, Laura Thomas, Patricia Mathieu, Pablo Carabias, Maria F Troncoso, Juana M Pasquini, Gabriel A Rabinovich, Laura A Pasquini
Galectin-1 (Gal-1), a member of a highly conserved family of animal lectins, binds to the common disaccharide [Galβ(1-4)-GlcNAc] on both N- and O-glycans decorating cell surface glycoconjugates. Current evidence supports a role for Gal-1 in the pathophysiology of multiple sclerosis (MS), one of the most prevalent chronic inflammatory diseases. Previous studies showed that Gal-1 exerts neuroprotective effects by promoting microglial deactivation in a model of autoimmune neuroinflammation and induces axonal regeneration in spinal cord injury...
September 6, 2016: Neurobiology of Disease
Nesli Ece Sen, Jessica Drost, Suzana Gispert, Sylvia Torres-Odio, Ewa Damrath, Michael Klinkenberg, Hamid Hamzeiy, Gülden Akdal, Halil Güllüoğlu, A Nazlı Başak, Georg Auburger
Ataxin-2 (ATXN2) polyglutamine domain expansions of large size result in an autosomal dominantly inherited multi-system-atrophy of the nervous system named spinocerebellar ataxia type 2 (SCA2), while expansions of intermediate size act as polygenic risk factors for motor neuron disease (ALS and FTLD) and perhaps also for Levodopa-responsive Parkinson's disease (PD). In view of the established role of ATXN2 for RNA processing in periods of cell stress and the expression of ATXN2 in blood cells such as platelets, we investigated whether global deep RNA sequencing of whole blood from SCA2 patients identifies a molecular profile which might serve as diagnostic biomarker...
September 3, 2016: Neurobiology of Disease
Candi L LaSarge, Raymund Y K Pun, Michael B Muntifering, Steve C Danzer
Abnormal hippocampal granule cells are present in patients with temporal lobe epilepsy, and are a prominent feature of most animal models of the disease. These abnormal cells are hypothesized to contribute to epileptogenesis. Isolating the specific effects of abnormal granule cells on hippocampal physiology, however, has been difficult in traditional temporal lobe epilepsy models. While epilepsy induction in these models consistently produces abnormal granule cells, the causative insults also induce widespread cell death among hippocampal, cortical and subcortical structures...
September 3, 2016: Neurobiology of Disease
Umberto Rodella, Michele Scorzeto, Elisa Duregotti, Samuele Negro, Bryan C Dickinson, Christopher J Chang, Nobuhiro Yuki, Michela Rigoni, Cesare Montecucco
The neuromuscular junction is a tripartite synapse composed of the presynaptic nerve terminal, the muscle and perisynaptic Schwann cells. Its functionality is essential for the execution of body movements and is compromised in a number of disorders, including Miller Fisher syndrome, a variant of Guillain-Barré syndrome: this autoimmune peripheral neuropathy is triggered by autoantibodies specific for the polysialogangliosides GQ1b and GT1a present in motor axon terminals, including those innervating ocular muscles, and in sensory neurons...
September 3, 2016: Neurobiology of Disease
Irene Sebastianutto, Natallia Maslava, Corey R Hopkins, M Angela Cenci
Rodent models of l-DOPA-induced dyskinesia (LID) are essential to investigate pathophysiological mechanisms and treatment options. Ratings of abnormal involuntary movements (AIMs) are used to capture both qualitative and quantitative features of dyskinetic behaviors. Thus far, validated rating scales for the mouse have anchored the definition of severity to the time during which AIMs are present. Here we have asked whether the severity of axial, limb, and orolingual AIMs can be objectively assessed with scores based on movement amplitude...
September 2, 2016: Neurobiology of Disease
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