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https://www.readbyqxmd.com/read/29313812/pathogenic-commonalities-between-spinal-muscular-atrophy-and-amyotrophic-lateral-sclerosis-converging-roads-to-therapeutic-development
#1
REVIEW
Melissa Bowerman, Lyndsay M Murrray, Frédérique Scamps, Bernard L Schneider, Rashmi Kothary, Cédric Raoul
Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are the two most common motoneuron disorders, which share typical pathological hallmarks while remaining genetically distinct. Indeed, SMA is caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene whilst ALS, albeit being mostly sporadic, can also be caused by mutations within genes, including superoxide dismutase 1 (SOD1), Fused in Sarcoma (FUS), TAR DNA-binding protein 43 (TDP-43) and chromosome 9 open reading frame 72 (C9ORF72)...
December 4, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/29308690/overexpression-of-a-conserved-hsp40-chaperone-reduces-toxicity-of-several-neurodegenerative-disease-proteins
#2
Sei-Kyoung Park, Fatih Arslan, Vydehi Kanneganti, Sami J Barmada, Pravinkumar Purushothaman, Subhash Chandra Verma, Susan W Liebman
TDP-43 and FUS are DNA/RNA binding proteins associated with neuronal inclusions in amyotrophic lateral sclerosis (ALS) patients. Other neurodegenerative diseases are also characterized by neuronal protein aggregates, e.g. Huntington's disease, associated with polyglutamine (polyQ) expansions in the protein huntingtin. Here we discuss our recent paper establishing similarities between aggregates of TDP-43 that have short glutamine and asparagine (Q/N)-rich modules and are soluble in detergents, with those of polyQ and PIN4C that have large Q/N-rich domains and are detergent-insoluble...
January 8, 2018: Prion
https://www.readbyqxmd.com/read/29243911/neurodegenerative-disease-proteinopathies-are-connected-to-distinct-histone-post-translational-modification-landscapes
#3
Karen Chen, Seth A Bennett, Navin Rana, Huda Yousuf, Mohamed Said, Sadiqa Taaseen, Natalie Mendo, Steven Marc Meltser, Mariana Torrente
Amyotrophic Lateral Sclerosis (ALS) and Parkinson's disease (PD) are devastating neurodegenerative diseases involving the progressive degeneration of neurons. No cure is available for patients diagnosed with these diseases. A prominent feature for both ALS and PD is the accumulation of protein inclusions in the cytoplasm of degenerating neurons; however, the particular protein comprising these inclusions varies. The RNA-binding proteins TDP-43 and FUS are most notable in ALS, while α-synuclein aggregates into Lewy bodies in PD...
December 15, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29221425/riluzole-does-not-improve-lifespan-or-motor-function-in-three-als-mouse-models
#4
Marion C Hogg, Luise Halang, Ina Woods, Karen S Coughlan, Jochen H M Prehn
BACKGROUND: Riluzole is the most widespread therapeutic for treatment of the progressive degenerative disease amyotrophic lateral sclerosis (ALS). Riluzole gained FDA approval in 1995 before the development of ALS mouse models. We assessed riluzole in three transgenic ALS mouse models: the SOD1G93A model, the TDP-43A315T model, and the recently developed FUS (1-359) model. METHODS: Age, sex and litter-matched mice were treated with riluzole (22 mg/kg) in drinking water or vehicle (DMSO) from symptom onset...
December 8, 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/29203801/de-novo-design-of-rna-binding-proteins-with-a-prion-like-domain-related-to-als-ftd-proteinopathies
#5
Kana Mitsuhashi, Daisuke Ito, Kyoko Mashima, Munenori Oyama, Shinichi Takahashi, Norihiro Suzuki
Aberrant RNA-binding proteins form the core of the neurodegeneration cascade in spectrums of disease, such as amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Six ALS-related molecules, TDP-43, FUS, TAF15, EWSR1, heterogeneous nuclear (hn)RNPA1 and hnRNPA2 are RNA-binding proteins containing candidate mutations identified in ALS patients and those share several common features, including harboring an aggregation-prone prion-like domain (PrLD) containing a glycine/serine-tyrosine-glycine/serine (G/S-Y-G/S)-motif-enriched low-complexity sequence and rich in glutamine and/or asparagine...
December 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29194538/mitochondrial-abnormalities-and-disruption-of-the-neuromuscular-junction-precede-the-clinical-phenotype-and-motor-neuron-loss-in-hfuswt-transgenic-mice
#6
Eva So, Jacqueline C Mitchell, Caroline Memmi, George Chennell, Gema Vizcay-Barrena, Leanne Allison, Christopher E Shaw, Caroline Vance
FUS mislocalisation and cytoplasmic aggregation are hallmark pathologies in FUS-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Many of the mechanistic hypotheses have focused on a loss of nuclear function in the FUS-opathies, implicating dysregulated RNA transcription and splicing in driving neurodegeneration. Recent studies describe an additional somato-dendritic localisation for FUS in the cerebral cortex implying a regulatory role in mRNA transport and local translation at the synapse...
November 28, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29140459/rbm45-competes-with-hdac1-for-binding-to-fus-in-response-to-dna-damage
#7
Juanjuan Gong, Min Huang, Fengli Wang, Xiaolu Ma, Hongmei Liu, Yingfeng Tu, Lingyu Xing, Xuefei Zhu, Hui Zheng, Junjie Fang, Xiaoling Li, Qiaochu Wang, Jiuqiang Wang, Zhongshuai Sun, Xi Wang, Yun Wang, Caixia Guo, Tie-Shan Tang
DNA damage response (DDR) is essential for genome stability and human health. Recently, several RNA binding proteins (RBPs), including fused-in-sarcoma (FUS), have been found unexpectedly to modulate this process. The role of FUS in DDR is closely linked to the pathogenesis of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Given that RBM45 is also an ALS-associated RBP, we wondered whether RBM45 plays any function during this process...
November 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29109432/als-associated-mutations-in-matrin-3-alter-protein-protein-interactions-and-impede-mrna-nuclear-export
#8
Ashley Boehringer, Krystine Garcia-Mansfield, Gurkaran Singh, Nadine Bakkar, Patrick Pirrotte, Robert Bowser
Mutations in Matrin 3 have recently been linked to ALS, though the mechanism that induces disease in these patients is unknown. To define the protein interactome of wild-type and ALS-linked MATR3 mutations, we performed immunoprecipitation followed by mass spectrometry using NSC-34 cells expressing human wild-type or mutant Matrin 3. Gene ontology analysis identified a novel role for Matrin 3 in mRNA transport centered on proteins in the TRanscription and EXport (TREX) complex, known to function in mRNA biogenesis and nuclear export...
November 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29102476/investigating-ccnf-mutations-in-a-taiwanese-cohort-with-amyotrophic-lateral-sclerosis
#9
Pei-Chien Tsai, Yi-Chu Liao, Po-Lin Chen, Yuh-Cherng Guo, Ying-Hao Chen, Kang-Yang Jih, Kon-Ping Lin, Bing-Wen Soong, Ching-Paio Tsai, Yi-Chung Lee
Mutations in the cyclin F gene (CCNF) have been recently identified in a small number of patients with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia, and their role in patients with ALS in Taiwan remains elusive. The aim of this study was to elucidate the frequency and spectrum of CCNF mutations in a Taiwanese ALS cohort of Han Chinese origin. Mutational analyses of the CCNF gene were performed using Sanger sequencing in a cohort of 255 unrelated patients with ALS. Among these patients, the genetic diagnoses of 204 patients remained unclear after mutations in SOD1, C9ORF72, TARDBP, FUS, ATXN2, OPTN, VCP, UBQLN2, SQSTM1, PFN1, HNRNPA1, HNRNPA2B1, MATR3, CHCHD10, TUBA4A, and TKB1 had been investigated...
October 9, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29053860/clinicopathological-correlations-in-behavioural-variant-frontotemporal-dementia
#10
David C Perry, Jesse A Brown, Katherine L Possin, Samir Datta, Andrew Trujillo, Anneliese Radke, Anna Karydas, John Kornak, Ana C Sias, Gil D Rabinovici, Maria Luisa Gorno-Tempini, Adam L Boxer, Mary De May, Katherine P Rankin, Virginia E Sturm, Suzee E Lee, Brandy R Matthews, Aimee W Kao, Keith A Vossel, Maria Carmela Tartaglia, Zachary A Miller, Sang Won Seo, Manu Sidhu, Stephanie E Gaus, Alissa L Nana, Jose Norberto S Vargas, Ji-Hye L Hwang, Rik Ossenkoppele, Alainna B Brown, Eric J Huang, Giovanni Coppola, Howard J Rosen, Daniel Geschwind, John Q Trojanowski, Lea T Grinberg, Joel H Kramer, Bruce L Miller, William W Seeley
Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system...
October 6, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29053787/humanized-mutant-fus-drives-progressive-motor-neuron-degeneration-without-aggregation-in-fusdelta14-knockin-mice
#11
Anny Devoy, Bernadett Kalmar, Michelle Stewart, Heesoon Park, Beverley Burke, Suzanna J Noy, Yushi Redhead, Jack Humphrey, Kitty Lo, Julian Jaeger, Alan Mejia Maza, Prasanth Sivakumar, Cinzia Bertolin, Gianni Soraru, Vincent Plagnol, Linda Greensmith, Abraham Acevedo Arozena, Adrian M Isaacs, Benjamin Davies, Pietro Fratta, Elizabeth M C Fisher
Mutations in FUS are causative for amyotrophic lateral sclerosis with a dominant mode of inheritance. In trying to model FUS-amyotrophic lateral sclerosis (ALS) in mouse it is clear that FUS is dosage-sensitive and effects arise from overexpression per se in transgenic strains. Novel models are required that maintain physiological levels of FUS expression and that recapitulate the human disease-with progressive loss of motor neurons in heterozygous animals. Here, we describe a new humanized FUS-ALS mouse with a frameshift mutation, which fulfils both criteria: the FUS Delta14 mouse...
November 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29035885/als-related-mutant-fus-protein-is-mislocalized-to-cytoplasm-and-is-recruited-into-stress-granules-of-fibroblasts-from-asymptomatic-fus-p525l-mutation-carriers
#12
Margherita Lo Bello, Francesca Di Fini, Antonietta Notaro, Rossella Spataro, Francesca L Conforti, Vincenzo La Bella
BACKGROUND: Amyotrophic lateral sclerosis (ALS) shows a strong genetic basis, with SOD1, FUS, TARDBP, and C9ORF72 being the genes most frequently involved. This has allowed identification of asymptomatic mutation carriers, which may be of help in understanding the molecular changes preceding disease onset. OBJECTIVES: We studied the cellular expression of FUS protein and the effect of heat-shock- and dithiothreitol-induced stress in fibroblasts from FUS P525L mutation carriers, healthy controls, and patients with sporadic ALS...
October 17, 2017: Neuro-degenerative Diseases
https://www.readbyqxmd.com/read/29031901/als-and-ftd-insights-into-the-disease-mechanisms-and-therapeutic-targets
#13
Rajka M Liscic
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The causes are still largely unknown and no effective treatment currently exists. It has been shown that FTLD may coexist with ALS. The overlap between ALS and frontotemporal dementia (FTD), the clinical syndrome associated with FTLD, occurs at clinical, genetic, and pathological levels. The hallmark proteins of the pathognomonic inclusions are SOD-1, TDP-43 or FUS, rarely the disease is caused by mutations in the respective genes...
October 12, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29021520/hdac6-inhibition-reverses-axonal-transport-defects-in-motor-neurons-derived-from-fus-als-patients
#14
Wenting Guo, Maximilian Naujock, Laura Fumagalli, Tijs Vandoorne, Pieter Baatsen, Ruben Boon, Laura Ordovás, Abdulsamie Patel, Marc Welters, Thomas Vanwelden, Natasja Geens, Tine Tricot, Veronick Benoy, Jolien Steyaert, Cynthia Lefebvre-Omar, Werend Boesmans, Matthew Jarpe, Jared Sterneckert, Florian Wegner, Susanne Petri, Delphine Bohl, Pieter Vanden Berghe, Wim Robberecht, Philip Van Damme, Catherine Verfaillie, Ludo Van Den Bosch
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder due to selective loss of motor neurons (MNs). Mutations in the fused in sarcoma (FUS) gene can cause both juvenile and late onset ALS. We generated and characterized induced pluripotent stem cells (iPSCs) from ALS patients with different FUS mutations, as well as from healthy controls. Patient-derived MNs show typical cytoplasmic FUS pathology, hypoexcitability, as well as progressive axonal transport defects. Axonal transport defects are rescued by CRISPR/Cas9-mediated genetic correction of the FUS mutation in patient-derived iPSCs...
October 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/28988989/fus-mutant-human-motoneurons-display-altered-transcriptome-and-microrna-pathways-with-implications-for-als-pathogenesis
#15
Riccardo De Santis, Laura Santini, Alessio Colantoni, Giovanna Peruzzi, Valeria de Turris, Vincenzo Alfano, Irene Bozzoni, Alessandro Rosa
The FUS gene has been linked to amyotrophic lateral sclerosis (ALS). FUS is a ubiquitous RNA-binding protein, and the mechanisms leading to selective motoneuron loss downstream of ALS-linked mutations are largely unknown. We report the transcriptome analysis of human purified motoneurons, obtained from FUS wild-type or mutant isogenic induced pluripotent stem cells (iPSCs). Gene ontology analysis of differentially expressed genes identified significant enrichment of pathways previously associated to sporadic ALS and other neurological diseases...
November 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28988390/topographic-distribution-of-brain-iron-deposition-and-small-cerebrovascular-lesions-in-amyotrophic-lateral-sclerosis-and-in-frontotemporal-lobar-degeneration-a-post-mortem-7-0-tesla-magnetic-resonance-imaging-study-with-neuropathological-correlates
#16
Jacques De Reuck, David Devos, Caroline Moreau, Florent Auger, Nicolas Durieux, Vincent Deramecourt, Florence Pasquier, Claude-Alain Maurage, Charlotte Cordonnier, Didier Leys, Regis Bordet
Amyotrophic lateral sclerosis (ALS) is associated with frontotemporal lobar degeneration (FTLD) in 15% of the cases. A neuropathological continuity between ALS and FTLD-TDP is suspected. The present post-mortem 7.0-tesla magnetic resonance imaging (MRI) study compares the topographic distribution of iron (Fe) deposition and the incidence of small cerebrovascular lesions in ALS and in FTLD brains. Seventy-eight post-mortem brains underwent 7.0-tesla MRI. The patients consisted of 12 with ALS, 38 with FTLD, and 28 controls...
October 7, 2017: Acta Neurologica Belgica
https://www.readbyqxmd.com/read/28987183/amyotrophic-lateral-sclerosis-and-non-tau-frontotemporal-lobar-degeneration
#17
Tibor Hortobágyi, Nigel J Cairns
Amyotrophic lateral sclerosis (ALS) is the major motor neuron disorder. The hallmark features are progressive, irreversible motor neuron loss leading to denervation atrophy of muscles and death, usually within 5 years of disease onset. The hallmark proteins of the pathognomonic inclusions are SOD-1, TDP-43, or FUS; rarely the disease is caused by mutation of the respective genes. Frontotemporal lobar degeneration (FTLD) is genetically, neuropathologically, and clinically heterogeneous and may present as a dementia with three major clinical syndromes dominated by behavioral, language, and motor disorders, respectively...
2017: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/28980860/the-roles-of-intrinsic-disorder-based-liquid-liquid-phase-transitions-in-the-dr-jekyll-mr-hyde-behavior-of-proteins-involved-in-amyotrophic-lateral-sclerosis-and-frontotemporal-lobar-degeneration
#18
Vladimir N Uversky
Pathological developments leading to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are associated with misbehavior of several key proteins, such as SOD1 (superoxide dismutase 1), TARDBP/TDP-43, FUS, C9orf72, and dipeptide repeat proteins generated as a result of the translation of the intronic hexanucleotide expansions in the C9orf72 gene, PFN1 (profilin 1), GLE1 (GLE1, RNA export mediator), PURA (purine rich element binding protein A), FLCN (folliculin), RBM45 (RNA binding motif protein 45), SS18L1/CREST, HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1), HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1), ATXN2 (ataxin 2), MAPT (microtubule associated protein tau), and TIA1 (TIA1 cytotoxic granule associated RNA binding protein)...
October 5, 2017: Autophagy
https://www.readbyqxmd.com/read/28973294/dysregulation-of-chromatin-remodelling-complexes-in-amyotrophic-lateral-sclerosis
#19
Michael Tibshirani, Beibei Zhao, Benoit J Gentil, Sandra Minotti, Christine Marques, Julia Keith, Ekaterina Rogaeva, Lorne Zinman, Caroline Rouaux, Janice Robertson, Heather D Durham
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with paralysis resulting from dysfunction and loss of motor neurons. A common neuropathological finding is attrition of motor neuron dendrites, which make central connections vital to motor control. The chromatin remodelling complex, neuronal Brahma-related gene 1 (Brg1)-associated factor complex (nBAF), is critical for neuronal differentiation, dendritic extension and synaptic function. We have identified loss of the crucial nBAF subunits Brg1, Brg1-associated factor 53b and calcium responsive transactivator in cultured motor neurons expressing FUS or TAR-DNA Binding Protein 43 (TDP-43) mutants linked to familial ALS...
November 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28969660/novel-mir-b2122-regulates-several-als-related-rna-binding-proteins
#20
Zachary C E Hawley, Danae Campos-Melo, Michael J Strong
Common pathological features of amyotrophic lateral sclerosis (ALS) include cytoplasmic aggregation of several RNA-binding proteins. Out of these RNA-binding proteins, TDP-43, FUS/TLS and RGNEF have been shown to co-aggregate with one another within motor neurons of sporadic ALS (sALS) patients, suggesting that there may be a common regulatory network disrupted. MiRNAs have been a recent focus in ALS research as they have been identified to be globally down-regulated in the spinal cord of ALS patients. The objective of this study was to identify if there are miRNA(s) dysregulated in sALS that are responsible for regulating the TDP-43, FUS/TLS and RGNEF network...
October 2, 2017: Molecular Brain
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