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https://www.readbyqxmd.com/read/28430856/a-comprehensive-analysis-of-rare-genetic-variation-in-amyotrophic-lateral-sclerosis-in-the-uk
#1
Sarah Morgan, Aleksey Shatunov, William Sproviero, Ashley R Jones, Maryam Shoai, Deborah Hughes, Ahmad Al Khleifat, Andrea Malaspina, Karen E Morrison, Pamela J Shaw, Christopher E Shaw, Katie Sidle, Richard W Orrell, Pietro Fratta, John Hardy, Alan Pittman, Ammar Al-Chalabi
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2...
April 18, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28429275/tgf-%C3%AE-1-neuroprotection-via-inhibition-of-microglial-activation-in-a-rat-model-of-parkinson-s-disease
#2
Xiao Chen, Zhan Liu, Bei-Bei Cao, Yi-Hua Qiu, Yu-Ping Peng
Transforming growth factor (TGF)-β1 is a pleiotropic cytokine with immunosuppressive and anti-inflammatory properties. Recently we have shown that TGF-β1 pretreatment in vitro protects against 1-methyl-4-phenylpyridinium (MPP(+))-induced dopaminergic neuronal loss that characterizes in Parkinson's disease (PD). Herein, we aimed to demonstrate that TGF-β1 administration in vivo after MPP(+) toxicity has neuroprotection that is achieved by a mediation of microglia. A rat model of PD was prepared by injecting MPP(+) unilaterally in the striatum...
April 20, 2017: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/28429106/occupational-exposure-to-extremely-low-frequency-magnetic-fields-and-risk-for-central-nervous-system-disease-an-update-of-a-danish-cohort-study-among-utility-workers
#3
Camilla Pedersen, Aslak Harbo Poulsen, Naja Hulvej Rod, Patrizia Frei, Johnni Hansen, Kathrine Grell, Ole Raaschou-Nielsen, Joachim Schüz, Christoffer Johansen
PURPOSE: Evidence of whether exposure to extremely low-frequency magnetic fields (ELF-MF) is related to central nervous system diseases is inconsistent. This study updates a previous study of the incidence of such diseases in a large cohort of Danish utility workers by almost doubling the period of follow-up. METHODS: We investigated the risks for dementia, motor neurone disease, Parkinson disease, multiple sclerosis and epilepsy among 32,006 men employed at the 99 utility companies that supplied Denmark with electricity during the period 1900-1993...
April 20, 2017: International Archives of Occupational and Environmental Health
https://www.readbyqxmd.com/read/28428745/decreased-levels-of-foldase-and-chaperone-proteins-are-associated-with-an-early-onset-amyotrophic-lateral-sclerosis
#4
Melania Filareti, Silvia Luotti, Laura Pasetto, Mauro Pignataro, Katia Paolella, Paolo Messina, Elisabetta Pupillo, Massimiliano Filosto, Christian Lunetta, Jessica Mandrioli, Giuseppe Fuda, Andrea Calvo, Adriano Chiò, Massimo Corbo, Caterina Bendotti, Ettore Beghi, Valentina Bonetto
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive upper and lower motor neuron degeneration. One of the peculiar clinical characteristics of ALS is the wide distribution in age of onset, which is probably caused by different combinations of intrinsic and exogenous factors. We investigated whether these modifying factors are converging into common pathogenic pathways leading either to an early or a late disease onset. This would imply the identification of phenotypic biomarkers, that can distinguish the two populations of ALS patients, and of relevant pathways to consider in a therapeutic intervention...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28428229/withdrawal-of-invasive-ventilation-in-a-patient-with-motor-neurone-disease-and-total-locked-in-syndrome
#5
Aoife Gleeson, Faye Johnson
Withdrawing invasive ventilation from a person with motor neurone disease who lacks the relevant mental capacity raises ethical issues such as the withdrawal of life-sustaining treatment and establishing best interests. There is little available information on providing optimal symptom management to these patients during the withdrawal process. We describe a man with motor neurone disease who also had total locked-in syndrome at the time of ventilation withdrawal, and we document the legal, ethical, emotional and symptom control issues encountered in supporting him...
April 20, 2017: Practical Neurology
https://www.readbyqxmd.com/read/28426667/bioenergetic-status-modulates-motor-neuron-vulnerability-and-pathogenesis-in-a-zebrafish-model-of-spinal-muscular-atrophy
#6
Penelope J Boyd, Wen-Yo Tu, Hannah K Shorrock, Ewout J N Groen, Roderick N Carter, Rachael A Powis, Sophie R Thomson, Derek Thomson, Laura C Graham, Anna A L Motyl, Thomas M Wishart, J Robin Highley, Nicholas M Morton, Thomas Becker, Catherina G Becker, Paul R Heath, Thomas H Gillingwater
Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles...
April 20, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28421535/microrna-metabolism-and-dysregulation-in-amyotrophic-lateral-sclerosis
#7
REVIEW
Paola Rinchetti, Mafalda Rizzuti, Irene Faravelli, Stefania Corti
MicroRNAs (miRNAs) are a subset of endogenous, small, non-coding RNA molecules involved in the post-transcriptional regulation of eukaryotic gene expression. Dysregulation in miRNA-related pathways in the central nervous system (CNS) is associated with severe neuronal injury and cell death, which can lead to the development of neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS). ALS is a fatal adult onset disease characterized by the selective loss of upper and lower motor neurons. While the pathogenesis of ALS is still largely unknown, familial ALS forms linked to TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS) gene mutations, as well as sporadic forms, display changes in several steps of RNA metabolism, including miRNA processing...
April 18, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28419739/cardiac-troponin-t-and-fast-skeletal-muscle-denervation-in-ageing
#8
Zherong Xu, Xin Feng, Juan Dong, Zhong-Min Wang, Jingyun Lee, Cristina Furdui, Daniel Clark Files, Kristen M Beavers, Stephen Kritchevsky, Carolanne Milligan, Jian-Ping Jin, Osvaldo Delbono, Tan Zhang
BACKGROUND: Ageing skeletal muscle undergoes chronic denervation, and the neuromuscular junction (NMJ), the key structure that connects motor neuron nerves with muscle cells, shows increased defects with ageing. Previous studies in various species have shown that with ageing, type II fast-twitch skeletal muscle fibres show more atrophy and NMJ deterioration than type I slow-twitch fibres. However, how this process is regulated is largely unknown. A better understanding of the mechanisms regulating skeletal muscle fibre-type specific denervation at the NMJ could be critical to identifying novel treatments for sarcopenia...
April 16, 2017: Journal of Cachexia, Sarcopenia and Muscle
https://www.readbyqxmd.com/read/28418693/validating-the-predicted-effect-of-astemizole-and-ketoconazole-using-a-drosophila-model-of-parkinson-s-disease
#9
Katarzyna Styczyńska-Soczka, Luigi Zechini, Lysimachos Zografos
Parkinson's disease is a growing threat to an ever-ageing population. Despite progress in our understanding of the molecular and cellular mechanisms underlying the disease, all therapeutics currently available only act to improve symptoms and do not stop the disease process. It is therefore imperative that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson's. Drug repurposing has been recognized as being equally as promising as de novo drug discovery in the field of neurodegeneration and Parkinson's disease specifically...
April 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28416596/microrna-profiling-reveals-marker-of-motor-neuron-disease-in-als-models
#10
Mariah L Hoye, Erica D Koval, Amy J Wegener, Theodore S Hyman, Chengran Yang, David R O'Brien, Rebecca L Miller, Tracy Cole, Kathleen M Schoch, Tao Shen, Tomonori Kunikata, Jean-Philippe Richard, David H Gutmann, Nicholas J Maragakis, Holly B Kordasiewicz, Joseph D Dougherty, Timothy M Miller
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by the loss of motor neurons (MNs) in the brain and spinal cord, leading to fatally debilitating weakness. Because this disease predominantly affects MNs, we aimed to characterize the distinct expression profile of that cell type in order to elucidate underlying disease mechanisms and identify novel targets that inform on MN health during ALS disease timecourse. microRNAs (miRNAs) are short, non-coding RNAs that can shape the expression profile of a cell and, consequently, often exhibit cell type enriched expression...
April 17, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28416595/nonsinusoidal-beta-oscillations-reflect-cortical-pathophysiology-in-parkinson-s-disease
#11
Scott R Cole, Roemer van der Meij, Erik J Peterson, Coralie de Hemptinne, Philip A Starr, Bradley Voytek
Oscillations in neural activity play a critical role in neural computation and communication. There is intriguing new evidence that the nonsinusoidal features of the oscillatory waveforms may inform underlying physiological and pathophysiological characteristics. Time-domain waveform analysis approaches stand in contrast to traditional Fourier-based methods, which alter or destroy subtle waveform features. Recently it has been shown that the waveform features of oscillatory beta (13-30 Hz) events-a prominent motor cortical oscillation-may reflect near-synchronous excitatory synaptic inputs onto cortical pyramidal neurons...
April 17, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28413711/high-throughput-sequencing-revealed-a-novel-setx-mutation-in-a-hungarian-patient-with-amyotrophic-lateral-sclerosis
#12
Kornélia Tripolszki, Dóra Török, David Goudenège, Katalin Farkas, Adrienn Sulák, Nóra Török, József I Engelhardt, Péter Klivényi, Vincent Procaccio, Nikoletta Nagy, Márta Széll
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of the motor neurons. To date, 126 genes have been implicated in ALS. Therefore, the heterogenous genetic background of ALS requires comprehensive genetic investigative approaches. METHODS: In this study, DNA from 28 Hungarian ALS patients was subjected to targeted high-throughput sequencing of the coding regions of three Mendelian ALS genes: FUS, SETX, and C9ORF72...
April 2017: Brain and Behavior
https://www.readbyqxmd.com/read/28412499/parkinsonism-and-dystonia-are-differentially-induced-by-modulation-of-different-territories-in-the-basal-ganglia
#13
Deepak Kumbhare, Kathryn L Holloway, Mark S Baron
Numerous clinical and experimental observations suggest that deficient neuronal signaling in the globus pallidus externa (GPe) is integral to both Parkinson's disease (PD) and dystonia. In our previous studies in jaundiced dystonic rats, widespread silencing of neurons in GP (rodent equivalent to GPe) preceded and persisted during dystonic motor activity. We therefore hypothesized that on a background of slow and highly irregular and bursty neuronal activity in GP, cortical motor drive produces profound inhibition of GP as the basis for action induced dystonia in Gunn rats...
April 12, 2017: Neuroscience
https://www.readbyqxmd.com/read/28412171/gender-specific-amelioration-of-sma-phenotype-upon-disruption-of-a-deep-intronic-structure-by-an-oligonucleotide
#14
Matthew D Howell, Eric W Ottesen, Natalia N Singh, Rachel L Anderson, Ravindra N Singh
Spinal muscular atrophy (SMA), the leading genetic disease of children, is caused by low levels of survival motor neuron (SMN) protein. Here, we employ A15/283, an antisense oligonucleotide targeting a deep intronic sequence/structure, to examine the impact of restoration of SMN in a mild SMA mouse model. We show gender-specific amelioration of tail necrosis upon subcutaneous administrations of A15/283 into SMA mice at postnatal days 1 and 3. We also demonstrate that a modest increase in SMN due to early administrations of A15/283 dramatically improves testicular development and spermatogenesis...
April 13, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28411118/regulation-of-motor-proteins-axonal-transport-deficits-and-adult-onset-neurodegenerative-diseases
#15
REVIEW
Scott T Brady, Gerardo A Morfini
Neurons affected in a wide variety of unrelated adult-onset neurodegenerative diseases (AONDs) typically exhibit a "dying back" pattern of degeneration, which is characterized by early deficits in synaptic function and neuritic pathology long before neuronal cell death. Consistent with this observation, multiple unrelated AONDs including Alzheimer's disease, Parkinson's disease, Huntington's disease, and several motor neuron diseases feature early alterations in kinase-based signaling pathways associated with deficits in axonal transport (AT), a complex cellular process involving multiple intracellular trafficking events powered by microtubule-based motor proteins...
April 11, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28410663/frontotemporal-dementia
#16
REVIEW
Nicholas T Olney, Salvatore Spina, Bruce L Miller
Frontotemporal dementia (FTD) is a heterogeneous disorder with distinct clinical phenotypes associated with multiple neuropathologic entities. Presently, the term FTD encompasses clinical disorders that include changes in behavior, language, executive control, and often motor symptoms. The core FTD spectrum disorders include behavioral variant FTD, nonfluent/agrammatic variant primary progressive aphasia, and semantic variant PPA. Related FTD disorders include frontotemporal dementia with motor neuron disease, progressive supranuclear palsy syndrome, and corticobasal syndrome...
May 2017: Neurologic Clinics
https://www.readbyqxmd.com/read/28409282/motor-neuron-vulnerability-and-resistance-in-amyotrophic-lateral-sclerosis
#17
REVIEW
Jik Nijssen, Laura H Comley, Eva Hedlund
In the fatal disease-amyotrophic lateral sclerosis (ALS)-upper (corticospinal) motor neurons (MNs) and lower somatic MNs, which innervate voluntary muscles, degenerate. Importantly, certain lower MN subgroups are relatively resistant to degeneration, even though pathogenic proteins are typically ubiquitously expressed. Ocular MNs (OMNs), including the oculomotor, trochlear and abducens nuclei (CNIII, IV and VI), which regulate eye movement, persist throughout the disease. Consequently, eye-tracking devices are used to enable paralysed ALS patients (who can no longer speak) to communicate...
April 13, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28409281/spinal-poly-ga-inclusions-in-a-c9orf72-mouse-model-trigger-motor-deficits-and-inflammation-without-neuron-loss
#18
Martin H Schludi, Lore Becker, Lillian Garrett, Tania F Gendron, Qihui Zhou, Franziska Schreiber, Bastian Popper, Leda Dimou, Tim M Strom, Juliane Winkelmann, Anne von Thaden, Kristin Rentzsch, Stephanie May, Meike Michaelsen, Benjamin M Schwenk, Jing Tan, Benedikt Schoser, Marianne Dieterich, Leonard Petrucelli, Sabine M Hölter, Wolfgang Wurst, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Thomas Klopstock, Thomas Arzberger, Dieter Edbauer
Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples...
April 13, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28408982/what-causes-amyotrophic-lateral-sclerosis
#19
REVIEW
Sarah Martin, Ahmad Al Khleifat, Ammar Al-Chalabi
Amyotrophic lateral sclerosis is a neurodegenerative disease predominantly affecting upper and lower motor neurons, resulting in progressive paralysis and death from respiratory failure within 2 to 3 years. The peak age of onset is 55 to 70 years, with a male predominance. The causes of amyotrophic lateral sclerosis are only partly known, but they include some environmental risk factors as well as several genes that have been identified as harbouring disease-associated variation. Here we review the nature, epidemiology, genetic associations, and environmental exposures associated with amyotrophic lateral sclerosis...
2017: F1000Research
https://www.readbyqxmd.com/read/28408866/post-translational-modifications-and-protein-quality-control-in-motor-neuron-and-polyglutamine-diseases
#20
REVIEW
Fabio Sambataro, Maria Pennuto
Neurodegenerative diseases, including motor neuron and polyglutamine (polyQ) diseases, are a broad class of neurological disorders. These diseases are characterized by neuronal dysfunction and death, and by the accumulation of toxic aggregation-prone proteins in the forms of inclusions and micro-aggregates. Protein quality control is a cellular mechanism to reduce the burden of accumulation of misfolded proteins, a function that results from the coordinated actions of chaperones and degradation systems, such as the ubiquitin-proteasome system (UPS) and autophagy-lysosomal degradation system...
2017: Frontiers in Molecular Neuroscience
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