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Motor neuron disease

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https://www.readbyqxmd.com/read/28344997/simple-derivation-of-spinal-motor-neurons-from-escs-ipscs-using-sendai-virus-vectors
#1
Kazuya Goto, Keiko Imamura, Kenichi Komatsu, Kohnosuke Mitani, Kazuhiro Aiba, Norio Nakatsuji, Makoto Inoue, Akihiro Kawata, Hirofumi Yamashita, Ryosuke Takahashi, Haruhisa Inoue
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal degenerative disorder of motor neurons (MNs). Embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) now help us to understand the pathomechanisms of ALS via disease modeling. Various methods to differentiate ESCs/iPSCs into MNs by the addition of signaling molecules have been reported. However, classical methods require multiple steps, and newer simple methods using the transduction of transcription factors run the risk of genomic integration of the vector genes...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28344074/aberrant-distributions-of-nuclear-pore-complex-proteins-in-als-mice-and-als-patients
#2
Jingwei Shang, Toru Yamashita, Yumiko Nakano, Ryuta Morihara, Xianghong Li, Tian Feng, Xia Liu, Yong Huang, Yusuke Fukui, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe
Nuclear pore complexes (NPCs) play important roles in traffic of molecules between the nucleus and cytoplasm, aberrant distributions of components of NPCs were demonstrated in C9orf72 amyotrophic lateral sclerosis (C9-ALS) patients, but it is elusive whether such abnormities are also the case with other cause of ALS disease. In the present study, we investigated the spatiotemporal distributions of RanGAP1 and 4 representative nucleoporins (GP210, NUP205, NUP107 and NUP50) of NPCs in human Cu/Zn superoxide dismutase-1 mutation transgenic (SOD1-Tg) mice and sporadic ALS patients...
March 23, 2017: Neuroscience
https://www.readbyqxmd.com/read/28343865/regulatory-role-of-rna-chaperone-tdp-43-for-rna-misfolding-and-repeat-associated-translation-in-sca31
#3
Taro Ishiguro, Nozomu Sato, Morio Ueyama, Nobuhiro Fujikake, Chantal Sellier, Akemi Kanegami, Eiichi Tokuda, Bita Zamiri, Terence Gall-Duncan, Mila Mirceta, Yoshiaki Furukawa, Takanori Yokota, Keiji Wada, J Paul Taylor, Christopher E Pearson, Nicolas Charlet-Berguerand, Hidehiro Mizusawa, Yoshitaka Nagai, Kinya Ishikawa
Microsatellite expansion disorders are pathologically characterized by RNA foci formation and repeat-associated non-AUG (RAN) translation. However, their underlying pathomechanisms and regulation of RAN translation remain unknown. We report that expression of expanded UGGAA (UGGAAexp) repeats, responsible for spinocerebellar ataxia type 31 (SCA31) in Drosophila, causes neurodegeneration accompanied by accumulation of UGGAAexp RNA foci and translation of repeat-associated pentapeptide repeat (PPR) proteins, consistent with observations in SCA31 patient brains...
March 18, 2017: Neuron
https://www.readbyqxmd.com/read/28343168/potential-skin-involvement-in-als-revisiting-charcot-s-observation-a-review-of-skin-abnormalities-in-als
#4
Bastien Paré, François Gros-Louis
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons of the brain and spinal cord, leading to progressive paralysis and death. Interestingly, many skin changes have been reported in ALS patients, but never as yet fully explained. These observations could be due to the common embryonic origin of the skin and neural tissue known as the ectodermal germ layer. Following the first observation in ALS patients' skin by Dr Charcot in the 19th century, in the absence of bedsores unlike other bedridden patients, other morphological and molecular changes have been observed...
March 25, 2017: Reviews in the Neurosciences
https://www.readbyqxmd.com/read/28343142/circuit-mechanisms-of-sleepiness-and-cataplexy-in-narcolepsy
#5
REVIEW
Sara Pintwala, John Peever
Narcolepsy is a debilitating sleep disorder caused by loss of orexin neurons in the lateral hypothalamus. Excessive daytime sleepiness and cataplexy are the major complaints in narcolepsy, and are associated with impaired quality of life. Although it is unclear how orexin loss causes sleepiness and cataplexy, animal models have been instrumental in identifying the neurobiological underpinnings of narcolepsy because they reliably recapitulate disease symptoms. Current evidence indicates that orexin cell loss causes sleepiness and cataplexy by destabilizing the ability of the circuits that initiate and sustain normal levels of arousal and motor activity...
March 23, 2017: Current Opinion in Neurobiology
https://www.readbyqxmd.com/read/28342750/mutation-of-the-caspase-3-cleavage-site-in-the-astroglial-glutamate-transporter-eaat2-delays-disease-progression-and-extends-lifespan-in-the-sod1-g93a-mouse-model-of-als
#6
Lauren Taylor Rosenblum, Shashirekha Shamamandri-Markandaiah, Biswarup Ghosh, Emily Foran, Angelo C Lepore, Piera Pasinelli, Davide Trotti
Downregulation in the astroglial glutamate transporter EAAT2 in amyotrophic lateral sclerosis (ALS) patients and mutant SOD1 mouse models of ALS is believed to contribute to the death of motor neurons by excitotoxicity. We previously reported that caspase-3 cleaves EAAT2 at a unique cleavage consensus site located in its c-terminus domain, a proteolytic cleavage that also occurs in vivo in the mutant SOD1 mouse model of ALS and leads to accumulation of a sumoylated EAAT2 C-Terminus fragment (CTE-SUMO1) beginning around onset of disease...
March 22, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28342748/rnai-of-arcrna-hsr%C3%AF-affects-sub-cellular-localization-of-drosophila-fus-to-drive-neurodiseases
#7
Luca Lo Piccolo, Masamitsu Yamaguchi
Defective RNA metabolism is common pathogenic mechanisms involved in neurological disorders. Indeed, a conspicuous feature of some neurodegenerative diseases is the loss of nuclear activities of RNA-binding proteins (RBPs) like Fused in sarcoma (FUS) and eventually, their accumulation in cytoplasmic proteinaceous inclusions. Long non-coding RNAs (lncRNAs) are emerging as important regulators of tissue physiology and disease processes, including neurological disorders. A subset of these lncRNAs is the core of nuclear bodies (NBs), which are the sites of RNA processing and sequestration of specific ribonucleoproteins (RNPs) complexes...
March 22, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28342444/acid-ceramidase-deficiency-in-mice-results-in-a-broad-range-of-central-nervous-system-abnormalities
#8
Jakub Sikora, Shaalee Dworski, E Ellen Jones, Mustafa A Kamani, Matthew C Micsenyi, Tomo Sawada, Pauline Le Faouder, Justine Bertrand-Michel, Aude Dupuy, Christopher K Dunn, Ingrid Cong Yang Xuan, Josefina Casas, Gemma Fabrias, David R Hampson, Thierry Levade, Richard R Drake, Jeffrey A Medin, Steven U Walkley
Farber disease is a rare autosomal recessive disorder caused by acid ceramidase deficiency that usually presents as early-onset progressive visceral and neurologic disease. To understand the neurologic abnormality, we investigated behavioral, biochemical, and cellular abnormalities in the central nervous system of Asah1(P361R/P361R) mice, which serve as a model of Farber disease. Behaviorally, the mutant mice had reduced voluntary locomotion and exploration, increased thigmotaxis, abnormal spectra of basic behavioral activities, impaired muscle grip strength, and defects in motor coordination...
April 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28339401/is-huntingtin-dispensable-in-the-adult-brain
#9
Jeh-Ping Liu, Scott O Zeitlin
Huntingtin (HTT) is an essential protein during early embryogenesis and the development of the central nervous system (CNS). Conditional knock-out of mouse Huntingtin (Htt) expression in the CNS beginning during neural development, as well as reducing Htt expression only during embryonic and early postnatal stages, results in neurodegeneration in the adult brain. These findings suggest that HTT is important for the development and/or maintenance of the CNS, but they do not address the question of whether HTT is required specifically in the adult CNS for its normal functions and/or homeostasis...
March 21, 2017: Journal of Huntington's Disease
https://www.readbyqxmd.com/read/28337412/differential-involvement-of-corticospinal-tract-cst-fibers-in-umn-predominant-als-patients-with-or-without-cst-hyperintensity-a-diffusion-tensor-tractography-study
#10
Venkateswaran Rajagopalan, Erik P Pioro
Diagnosis of amyotrophic lateral sclerosis (ALS) depends on clinical evidence of combined upper motor neuron (UMN) and lower motor neuron (LMN) degeneration, although ALS patients can present with features predominantly of one or the other. Some UMN-predominant patients show hyperintense signal along the intracranial corticospinal tract (CST) on T2- and proton density (PD)-weighted images (ALS-CST +), and appear to have faster disease progression when compared to those without CST hyperintensity (ALS-CST -)...
2017: NeuroImage: Clinical
https://www.readbyqxmd.com/read/28337258/neuroprotective-effect-of-win55-212-2-against-3-nitropropionic-acid-induced-toxicity-in-the-rat-brain-involvement-of-cb1-and-nmda-receptors
#11
Marisol Maya-López, Ana Laura Colín-González, Gabriela Aguilera, María Eduarda de Lima, Ana Colpo-Ceolin, Edgar Rangel-López, Juana Villeda-Hernández, Daniel Rembao-Bojórquez, Isaac Túnez, Armando Luna-López, Roberto Lazzarini-Lechuga, Viridiana Yazmín González-Puertos, Pedro Posadas-Rodríguez, Alejandro Silva-Palacios, Mina Königsberg, Abel Santamaría
The endocannabinoid system (ECS), and agonists acting on cannabinoid receptors (CBr), are known to regulate several physiological events in the brain, including modulatory actions on excitatory events probably through N-methyl-D-aspartate receptor (NMDAr) activity. Actually, CBr agonists can be neuroprotective. The synthetic CBr agonist WIN55,212-2 acts mainly on CB1 receptor. In turn, the mitochondrial toxin 3-nitropropionic acid (3-NP) produces striatal alterations in rats similar to those observed in the brain of Huntington's disease patients...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28336814/airway-smooth-muscle-dysfunction-in-pompe-gaa-mice
#12
Allison M Keeler, Donghai Liu, Marina Zieger, Lang Xiong, Jeffrey Salemi, Karl Bellve, Barry J Byrne, David D Fuller, Ronghua ZhuGe, Mai K ElMallah
Pompe disease is an autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase (GAA) - an enzyme responsible for hydrolyzing lysosomal glycogen. Deficiency of GAA leads to systemic glycogen accumulation in the lysosomes of skeletal muscle, motor neurons and smooth muscle. Skeletal muscle and motor neuron pathology are known to contribute to respiratory insufficiency in Pompe disease, but the role of airway pathology has not been evaluated. Here we propose that GAA enzyme deficiency disrupts the function of the trachea and bronchi, and this lower airway pathology contributes to respiratory insufficiency in Pompe disease...
March 23, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28336338/knockdown-of-appl-mimics-transgenic-a%C3%AE-induced-neurodegenerative-phenotypes-in-drosophila
#13
Sandeep Kumar Singh, Saurabh Srivastav, Amarish Kumar Yadav, Saripella Srikrishna
A variety of Drosophila mutant lines have been established as potential disease-models to study various disease mechanisms including human neurodegenerative diseases like Alzheimer's disease (AD), Huntington's disease (HD) and Parkinson's disease (PD). The evolutionary conservation of APP (Amyloid Precursor Protein) and APPL (Amyloid Precursor Protein-Like) and the comparable detrimental effects caused by their metabolic products strongly implies the conservation of their normal physiological functions. In view of this milieu, a comparative analysis on the pattern of neurodegenerative phenotypes between Drosophila APPL-RNAi line and transgenic Drosophila line expressing eye tissue specific human Aβ (Amyloid beta) was undertaken...
March 20, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28335910/management-strategies-for-cln2-disease
#14
REVIEW
Ruth E Williams, Heather R Adams, Martin Blohm, Jessica L Cohen-Pfeffer, Emily de Los Reyes, Jonas Denecke, Kristen Drago, Charlie Fairhurst, Margie Frazier, Norberto Guelbert, Szilárd Kiss, Annamaria Kofler, John A Lawson, Lenora Lehwald, Mary-Anne Leung, Svetlana Mikhaylova, Jonathan W Mink, Miriam Nickel, Renée Shediac, Katherine Sims, Nicola Specchio, Meral Topcu, Ina von Löbbecke, Andrea West, Boris Zernikow, Angela Schulz
CLN2 disease (neuronal ceroid lipofuscinosis type 2) is a rare, autosomal recessive, pediatric-onset, rapidly progressive neurodegenerative lysosomal storage disorder caused by tripeptidyl peptidase 1 (TPP1) enzyme deficiency, and is characterized by language delay, seizures, rapid cognitive and motor decline, blindness, and early death. No management guidelines exist and there is a paucity of published disease-specific evidence to inform clinical practice, which currently draws upon experience from the field of childhood neurodisability...
April 2017: Pediatric Neurology
https://www.readbyqxmd.com/read/28334938/clinical-and-genetic-characterization-of-leukoencephalopathies-in-adults
#15
David S Lynch, Anderson Rodrigues Brandão de Paiva, Wei Jia Zhang, Enrico Bugiardini, Fernando Freua, Leandro Tavares Lucato, Lucia Inês Macedo-Souza, Rahul Lakshmanan, Justin A Kinsella, Aine Merwick, Alexander M Rossor, Nin Bajaj, Brian Herron, Paul McMonagle, Patrick J Morrison, Deborah Hughes, Alan Pittman, Matilde Laurà, Mary M Reilly, Jason D Warren, Catherine J Mummery, Jonathan M Schott, Matthew Adams, Nick C Fox, Elaine Murphy, Indran Davagnanam, Fernando Kok, Jeremy Chataway, Henry Houlden
Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all...
March 2, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28334913/tdp-43-mutations-causing-amyotrophic-lateral-sclerosis-are-associated-with-altered-expression-of-rna-binding-protein-hnrnp-k-and-affect-the-nrf2-antioxidant-pathway
#16
Diane Moujalled, Alexandra Grubman, Karla Acevedo, Shu Yang, Yazi D Ke, Donia M Moujalled, Clare Duncan, Aphrodite Caragounis, Nirma D Perera, Bradley J Turner, Mercedes Prudencio, Leonard Petrucelli, Ian Blair, Lars M Ittner, Peter J Crouch, Jeffrey R Liddell, Anthony R White
TAR DNA binding protein 43 (TDP-43) is a major disease-associated protein involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Our previous studies found a direct association between TDP-43 and heterogeneous nuclear ribonucleoprotein K (hnRNP K). In this study, utilizing ALS patient fibroblasts harboring a TDP-43M337V mutation and NSC-34 motor neuronal cell line expressing TDP-43Q331K mutation, we show that hnRNP K expression is impaired in urea soluble extracts from mutant TDP-43 cell models...
March 9, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28334866/c9orf72-and-rab7l1-regulate-vesicle-trafficking-in-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia
#17
Yoshitsugu Aoki, Raquel Manzano, Yi Lee, Ruxandra Dafinca, Misako Aoki, Andrew G L Douglas, Miguel A Varela, Chaitra Sathyaprakash, Jakub Scaber, Paola Barbagallo, Pieter Vader, Imre Mäger, Kariem Ezzat, Martin R Turner, Naoki Ito, Samanta Gasco, Norihiko Ohbayashi, Samir El Andaloussi, Shin'ichi Takeda, Mitsunori Fukuda, Kevin Talbot, Matthew J A Wood
A non-coding hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), however, the precise molecular mechanism by which the C9orf72 hexanucleotide repeat expansion directs C9ALS/FTD pathogenesis remains unclear. Here, we report a novel disease mechanism arising due to the interaction of C9ORF72 with the RAB7L1 GTPase to regulate vesicle trafficking. Endogenous interaction between C9ORF72 and RAB7L1 was confirmed in human SH-SY5Y neuroblastoma cells...
February 23, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28334424/frequency-and-function-in-the-basal-ganglia-the-origins-of-beta-and-gamma-band-activity
#18
Alexander Blenkinsop, Sean Anderson, Kevin Gurney
Neural oscillations in the basal ganglia are well studied yet remain poorly understood. Behavioural correlates of spectral activity are well described, yet a quantitative hypothesis linking time domain dynamics and spectral properties to basal ganglia function has been lacking. We show, for the first time, that a unified description is possible by interpreting previously ignored structure in data describing GPi responses to cortical stimulation. These data were used to expose a pair of distinctive neuronal responses to the stimulation...
March 23, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28332824/indole-substituted-benzothiazoles-and-benzoxazoles-as-selective-and-reversible-mao-b-inhibitors-for-treatment-of-parkinson-s-disease
#19
Min-Ho Nam, Moosung Park, Hyeri Park, Youngjae Kim, Seulki Yoon, Vikram Shahaji Sawant, Ji Won Choi, Jong-Hyun Park, Ki Duk Park, Sun-Joon Min, Changjoon Justin Lee, Hyunah Choo
To develop a novel, selective, and reversible MAO-B inhibitors for safer treatment of Parkinson's disease, benzothiazole and benzoxazole derivatives with indole moiety were designed and synthesized. Most of the synthesized compounds showed inhibitory activities against MAO-B and selectivity over MAO-A. The most active compound was Compound 5b, 6-fluoro-2-(1-methyl-1H-indol-5-yl)benzo[d]thiazole with an IC50 value of 29 nM with no apparent effect on MAO-A activity at 10 M. Based on the reversibility assay, Compound 5b turned out to be a fully reversible with over 95% of recovery of enzyme activity after washout of the compound...
March 23, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28332488/parkinson-disease
#20
REVIEW
Werner Poewe, Klaus Seppi, Caroline M Tanner, Glenda M Halliday, Patrik Brundin, Jens Volkmann, Anette-Eleonore Schrag, Anthony E Lang
Parkinson disease is the second-most common neurodegenerative disorder that affects 2-3% of the population ≥65 years of age. Neuronal loss in the substantia nigra, which causes striatal dopamine deficiency, and intracellular inclusions containing aggregates of α-synuclein are the neuropathological hallmarks of Parkinson disease. Multiple other cell types throughout the central and peripheral autonomic nervous system are also involved, probably from early disease onwards. Although clinical diagnosis relies on the presence of bradykinesia and other cardinal motor features, Parkinson disease is associated with many non-motor symptoms that add to overall disability...
March 23, 2017: Nature Reviews. Disease Primers
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