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https://www.readbyqxmd.com/read/29666246/large-sod1-aggregates-unlike-trimeric-sod1-do-not-impact-cell-viability-in-a-model-of-amyotrophic-lateral-sclerosis
#1
Cheng Zhu, Matthew V Beck, Jack D Griffith, Mohanish Deshmukh, Nikolay V Dokholyan
Aberrant accumulation of misfolded Cu, Zn superoxide dismutase (SOD1) is a hallmark of SOD1-associated amyotrophic lateral sclerosis (ALS), an invariably fatal neurodegenerative disease. While recent discovery of nonnative trimeric SOD1-associated neurotoxicity has suggested a potential pathway for motor neuron impairment, it is yet unknown whether large, insoluble aggregates are cytotoxic. Here we designed SOD1 mutations that specifically stabilize either the fibrillar form or the trimeric state of SOD1. The designed mutants display elevated populations of fibrils or trimers correspondingly, as demonstrated by gel filtration chromatography and electron microscopy...
April 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29665503/zebrafish-extracellular-matrix-improves-neuronal-viability-and-network-formation-in-a-3-dimensional-culture
#2
Sung-Min Kim, Daniel Ward Long, Michael Wai Kok Tsang, Yadong Wang
Mammalian central nervous system (CNS) has limited capacity for regeneration. CNS injuries cause life-long debilitation and lead to $50 billion in healthcare costs in U.S. alone each year. Despite numerous efforts in the last few decades, CNS-related injuries remain as detrimental as they were 50 years ago. Some functional recovery can occur, but most regeneration are limited by an extracellular matrix (ECM) that actively inhibits axonal repair and promotes glial scarring. In most tissues, the ECM is an architectural foundation that plays an active role in supporting cellular development and regenerative response after injury...
April 6, 2018: Biomaterials
https://www.readbyqxmd.com/read/29656478/transplantation-of-neural-progenitor-cells-expressing-glial-cell-line-derived-neurotrophic-factor-into-the-motor-cortex-as-a-strategy-to-treat-amyotrophic-lateral-sclerosis
#3
Gretchen M Thomsen, Pablo Avalos, Annie A Ma, Mor Alkaslasi, Noell Cho, Livia Wyss, Jean-Philippe Vit, Marlesa Godoy, Patrick Suezaki, Oksana Shelest, Krystof S Bankiewicz, Clive N Svendsen
Early dysfunction of cortical motor neurons may underlie the initiation of amyotrophic lateral sclerosis (ALS). As such, the cortex represents a critical area of ALS research and a promising therapeutic target. In the current study, human cortical-derived neural progenitor cells engineered to secrete glial cell line-derived neurotrophic factor (GDNF) were transplanted into the SOD1G93A ALS rat cortex, where they migrated, matured into astrocytes, and released GDNF. This protected motor neurons, delayed disease pathology and extended survival of the animals...
April 15, 2018: Stem Cells
https://www.readbyqxmd.com/read/29653186/constraint-induced-movement-therapy-improves-efficacy-of-task-specific-training-after-severe-cortical-stroke-depending-on-the-ipsilesional-corticospinal-projections
#4
Naohiko Okabe, Naoyuki Himi, Emi Nakamura-Maruyama, Norito Hayashi, Issei Sakamoto, Kazuhiko Narita, Toru Hasegawa, Osamu Miyamoto
Descending spinal pathways (corticospinal, rubrospinal, and reticulospinal) are believed to contribute to functional recovery resulting from rehabilitative training after stroke. However, the contribution of each pathway remains unclear. In the current study, we investigated rehabilitation-induced functional recovery and remodelling of the descending spinal pathways after severe cortical stroke in rats followed by 3 weeks of various rehabilitation [constraint-induced movement therapy (CIMT), skilled forelimb reaching, rotarod, and treadmill exercise]...
April 10, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29649521/modelling-motor-neuron-disease-in-fruit-flies-lessons-from-spinal-muscular-atrophy
#5
Beppe Aquilina, Ruben J Cauchi
Motor neuron disease (MND) is characterised by muscle weakness and paralysis downstream of motor neuron degeneration. Genetic factors play a major role in disease pathogenesis and progression. This is best underscored by spinal muscular atrophy (SMA), the most common MND affecting children. Although SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene, partial compensation by the paralogous SMN2 gene and/or genetic modifiers influence age of onset and disease severity. SMA is also the first MND that is treatable thanks to the recent development of a molecular-based therapy...
April 9, 2018: Journal of Neuroscience Methods
https://www.readbyqxmd.com/read/29645362/structural-plasticity-of-the-tdrd3-tudor-domain-probed-by-a-fragment-screening-hit
#6
Jiuyang Liu, Shuya Zhang, Mingqing Liu, Yaqian Liu, Gilbert Nshogoza, Jia Gao, Rongsheng Ma, Yang Yang, Jihui Wu, Jiahai Zhang, Fudong Li, Ke Ruan
As a reader of di-methylated arginine on various proteins, such as histone, RNA polymerase II, PIWI and Fragile X mental retardation protein, the Tudor domain of Tudor domain-containing protein 3 (TDRD3) mediates transcriptional activation in nucleus and formation of stress granules in the cytoplasm. Despite the TDRD3 implication in cancer cell proliferation and invasion, warheads to block the di-methylated arginine recognition pocket of the TDRD3 Tudor domain have not yet been uncovered. Here we identified 14 small molecule hits against the TDRD3 Tudor domain through NMR fragment-based screening...
April 12, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29645329/modulating-the-folding-landscape-of-superoxide-dismutase-1-with-targeted-molecular-binders
#7
David Nelson Bunck, Beatriz Atsavapranee, Anna K Museth, David VanderVelde, James Richard Heath
Amyotrophic lateral sclerosis, or Lou Gehrig's disease, is characterized by motor neuron death with average survival times of 2 - 5 years. One cause of this disease is the misfolding of superoxide dismutase 1 (SOD1), a protein whose stability and aggregation propensity are affected by point mutations spanning the protein. Here, we use an epitope-specific, high-throughput screen to identify peptides that both stabilize the native conformation of SOD1 as well as accelerate its folding by 2.5-fold. Ligands targeted to the electrostatic loop on the periphery of the protein tightened the non-metalated structure and accelerated its folding...
April 12, 2018: Angewandte Chemie
https://www.readbyqxmd.com/read/29643503/functional-circuit-architecture-underlying-parental-behaviour
#8
Johannes Kohl, Benedicte M Babayan, Nimrod D Rubinstein, Anita E Autry, Brenda Marin-Rodriguez, Vikrant Kapoor, Kazunari Miyamishi, Larry S Zweifel, Liqun Luo, Naoshige Uchida, Catherine Dulac
Parenting is essential for the survival and wellbeing of mammalian offspring. However, we lack a circuit-level understanding of how distinct components of this behaviour are coordinated. Here we investigate how galanin-expressing neurons in the medial preoptic area (MPOAGal ) of the hypothalamus coordinate motor, motivational, hormonal and social aspects of parenting in mice. These neurons integrate inputs from a large number of brain areas and the activation of these inputs depends on the animal's sex and reproductive state...
April 11, 2018: Nature
https://www.readbyqxmd.com/read/29642434/a-single-dose-of-atorvastatin-applied-acutely-after-spinal-cord-injury-suppresses-inflammation-apoptosis-and-promotes-axon-outgrowth-which-might-be-essential-for-favorable-functional-outcome
#9
Katarina Bimbova, Maria Bacova, Alexandra Kisucka, Jaroslav Pavel, Jan Galik, Peter Zavacky, Martin Marsala, Andrea Stropkovska, Jana Fedorova, Stefania Papcunova, Jana Jachova, Nadezda Lukacova
The aim of our study was to limit the inflammatory response after a spinal cord injury (SCI) using Atorvastatin (ATR), a potent inhibitor of cholesterol biosynthesis. Adult Wistar rats were divided into five experimental groups: one control group, two Th9 compression (40 g/15 min) groups, and two Th9 compression + ATR (5 mg/kg, i.p.) groups. The animals survived one day and six weeks. ATR applied in a single dose immediately post-SCI strongly reduced IL-1β release at 4 and 24 h and considerably reduced the activation of resident cells at one day post-injury...
April 7, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29628395/hpsc-derived-striatal-cells-generated-using-a-scalable-3d-hydrogel-promote-recovery-in-a-huntington-disease-mouse-model
#10
Maroof M Adil, Thomas Gaj, Antara T Rao, Rishikesh U Kulkarni, Christina M Fuentes, Gokul N Ramadoss, Freja K Ekman, Evan W Miller, David V Schaffer
Huntington disease (HD) is an inherited, progressive neurological disorder characterized by degenerating striatal medium spiny neurons (MSNs). One promising approach for treating HD is cell replacement therapy, where lost cells are replaced by MSN progenitors derived from human pluripotent stem cells (hPSCs). While there has been remarkable progress in generating hPSC-derived MSNs, current production methods rely on two-dimensional culture systems that can include poorly defined components, limit scalability, and yield differing preclinical results...
April 3, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29621978/high-frequency-of-the-tardbp-p-m337-v-mutation-among-south-eastern-chinese-patients-with-familial-amyotrophic-lateral-sclerosis
#11
Guo-Rong Xu, Wei Hu, Ling-Ling Zhan, Chong Wang, Liu-Qing Xu, Min-Ting Lin, Wan-Jin Chen, Ning Wang, Qi-Jie Zhang
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease characterized by substantial clinical and genetic heterogeneity. Thus far, only a few TARDBP-ALS families have been reported in China, and no mutation analysis has been reported in south-eastern China. METHODS: Seven index cases from ALS families negative for SOD1 and FUS mutations were screened by Sanger sequencing for TARDBP gene exons 2-6. TARDBP exon 6 was analysed in 215 sporadic ALS patients...
April 5, 2018: BMC Neurology
https://www.readbyqxmd.com/read/29618588/sleep-active-neurons-conserved-motors-of-sleep
#12
REVIEW
Henrik Bringmann
Sleep is crucial for survival and well-being. This behavioral and physiological state has been studied in all major genetically accessible model animals, including rodents, fish, flies, and worms. Genetic and optogenetic studies have identified several neurons that control sleep, making it now possible to compare circuit mechanisms across species. The "motor" of sleep across animal species is formed by neurons that depolarize at the onset of sleep to actively induce this state by directly inhibiting wakefulness...
April 2018: Genetics
https://www.readbyqxmd.com/read/29614695/treatment-algorithm-for-infants-diagnosed-with-spinal-muscular-atrophy-through-newborn-screening
#13
Jacqueline Glascock, Jacinda Sampson, Amanda Haidet-Phillips, Anne Connolly, Basil Darras, John Day, Richard Finkel, R Rodney Howell, Katherine Klinger, Nancy Kuntz, Thomas Prior, Perry B Shieh, Thomas Crawford, Doug Kerr, Jill Jarecki
BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of alpha motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron 1 gene (SMN1). In humans, a nearly identical copy gene, SMN2, is present. Because SMN2 has been shown to decrease disease severity in a dose-dependent manner, SMN2 copy number is predictive of disease severity. OBJECTIVE: To develop a treatment algorithm for SMA-positive infants identified through newborn screening based upon SMN2 copy number...
March 26, 2018: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/29611555/endolysosomal-pathway-activity-protects-cells-from-neurotoxic-tdp-43
#14
COMMENT
Christine Leibiger, Jana Deisel, Andreas Aufschnaiter, Stefanie Ambros, Maria Tereshchenko, Bert M Verheijen, Sabrina Büttner, Ralf J Braun
The accumulation of protein aggregates in neurons is a typical pathological hallmark of the motor neuron disease amyotrophic lateral sclerosis (ALS) and of frontotemporal dementia (FTD). In many cases, these aggregates are composed of the 43 kDa TAR DNA-binding protein (TDP 43). Using a yeast model for TDP 43 proteinopathies, we observed that the vacuole (the yeast equivalent of lysosomes) markedly contributed to the degradation of TDP 43. This clearance occurred via TDP 43-containing vesicles fusing with the vacuole through the concerted action of the endosomal-vacuolar (or endolysosomal) pathway and autophagy...
March 21, 2018: Microbial Cell
https://www.readbyqxmd.com/read/29610000/critical-period-of-neuromuscular-development-importance-for-a-new-treatment-of-sma
#15
REVIEW
Gerta Vrbová, Urszula Sławińska
Findings from mice that had their Smn gene deleted and some copies of the human SMN2 gene introduced to produce SMN protein are summarized. Symptoms due to this manipulation can be corrected only by restoring the SMN protein expression in neurones and not in muscle. The changes in muscle and neuromuscular junction (NMJ) in these mutant mice are probably due to the malfunction of the neuronal component of the NMJ i.e. the nerve terminal. The reduction of transmitter release by nerve terminals in animals with reduced SMN protein supports this notion...
March 13, 2018: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/29609497/a-novel-d90_k91insn-mutation-in-exon-4-of-the-sod1-gene-caused-familial-amyotrophic-lateral-sclerosis-in-a-chinese-pedigree
#16
Yanran Li, Bo Sun, Siyu Chen, Yuting Ren, Fang Cui, Fei Yang, Zhaohui Chen, Li Ling, Xusheng Huang
We reported a novel heterozygous duplication mutation (c.272_274dupACA, D90_K91insN) in exon 4 of the SOD1 gene in a Chinese pedigree. This pedigree demonstrates an autosomal dominant pattern of inheritance, with potentially reduced penetrance. The clinical phenotype was rather uniform with a distal lower extremity onset, predominant involvement of lower motor neurons (LMNs), and a relatively short survival time (mean 2.6 years) compared with other mutations in the loop V structure of SOD1. We also detected that the average SOD1 activity in D90_K91insN mutation carriers is 68...
April 2, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/29606582/kir4-1-dependent-astrocyte-fast-motor-neuron-interactions-are-required-for-peak-strength
#17
Kevin W Kelley, Lucile Ben Haim, Lucas Schirmer, Giulia E Tyzack, Michaela Tolman, John G Miller, Hui-Hsin Tsai, Sandra M Chang, Anna V Molofsky, Yongjie Yang, Rickie Patani, Andras Lakatos, Erik M Ullian, David H Rowitch
Diversified neurons are essential for sensorimotor function, but whether astrocytes become specialized to optimize circuit performance remains unclear. Large fast α-motor neurons (FαMNs) of spinal cord innervate fast-twitch muscles that generate peak strength. We report that ventral horn astrocytes express the inward-rectifying K+ channel Kir4.1 (a.k.a. Kcnj10) around MNs in a VGLUT1-dependent manner. Loss of astrocyte-encoded Kir4.1 selectively altered FαMN size and function and led to reduced peak strength...
March 28, 2018: Neuron
https://www.readbyqxmd.com/read/29603689/cim-journal-club-gene-therapy-for-spinal-muscular-atrophy-comment-on-mendell-et-al-n-engl-j-med-2017-377-1713-22
#18
Raphael Schneider
In their landmark paper, Mendell et al. show that infants with spinal muscular atrophy (SMA) reached important motor milestones and survived longer when treated with AVXS-101 (AveXis), a viral vector containing DNA encoding the survival of motor neuron protein (SMN). Patients not only crawled, stood and walked independently, but learned to speak. These results are very encouraging for patients with SMA and offer hope for pediatric and adult patients with other types of motor neuron diseases.
March 27, 2018: Clinical and Investigative Medicine. Médecine Clinique et Experimentale
https://www.readbyqxmd.com/read/29602490/epidermal-growth-factor-regulates-apoptosis-and-oxidative-stress-in-a-rat-model-of-spinal-cord-injury
#19
Anil Murat Ozturk, Murat Celal Sozbilen, Elvin Sevgili, Taner Dagci, Halit Özyalcin, Guliz Armagan
Spinal cord injury (SCI) leads to vascular damage and disruption of blood-spinal cord barrier which participates in secondary nerve injury. Epidermal growth factor (EGF) is an endogenous protein which regulates cell proliferation, growth and differention. Previous studies reported that EGF exerts neuroprotective effect in spinal cord after SCI. However, the molecular mechanisms underlying EGF-mediated protection in different regions of nervous system have not shown yet. In this study, we aimed to examine possible anti-apoptotic and protective roles of EGF not only in spinal cord but also in brain following SCI...
March 22, 2018: Injury
https://www.readbyqxmd.com/read/29598923/prognosis-for-patients-with-amyotrophic-lateral-sclerosis-development-and-validation-of-a-personalised-prediction-model
#20
Henk-Jan Westeneng, Thomas P A Debray, Anne E Visser, Ruben P A van Eijk, James P K Rooney, Andrea Calvo, Sarah Martin, Christopher J McDermott, Alexander G Thompson, Susana Pinto, Xenia Kobeleva, Angela Rosenbohm, Beatrice Stubendorff, Helma Sommer, Bas M Middelkoop, Annelot M Dekker, Joke J F A van Vugt, Wouter van Rheenen, Alice Vajda, Mark Heverin, Mbombe Kazoka, Hannah Hollinger, Marta Gromicho, Sonja Körner, Thomas M Ringer, Annekathrin Rödiger, Anne Gunkel, Christopher E Shaw, Annelien L Bredenoord, Michael A van Es, Philippe Corcia, Philippe Couratier, Markus Weber, Julian Grosskreutz, Albert C Ludolph, Susanne Petri, Mamede de Carvalho, Philip Van Damme, Kevin Talbot, Martin R Turner, Pamela J Shaw, Ammar Al-Chalabi, Adriano Chiò, Orla Hardiman, Karel G M Moons, Jan H Veldink, Leonard H van den Berg
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, fatal motor neuron disease with a variable natural history. There are no accurate models that predict the disease course and outcomes, which complicates risk assessment and counselling for individual patients, stratification of patients for trials, and timing of interventions. We therefore aimed to develop and validate a model for predicting a composite survival endpoint for individual patients with ALS. METHODS: We obtained data for patients from 14 specialised ALS centres (each one designated as a cohort) in Belgium, France, the Netherlands, Germany, Ireland, Italy, Portugal, Switzerland, and the UK...
March 26, 2018: Lancet Neurology
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