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https://www.readbyqxmd.com/read/29774215/importance-of-functional-loss-of-fus-in-ftld-als
#1
REVIEW
Shinsuke Ishigaki, Gen Sobue
Fused in sarcoma (FUS) is an RNA binding protein that regulates RNA metabolism including alternative splicing, transcription, and RNA transportation. FUS is genetically and pathologically involved in frontotemporal lobar degeneration (FTLD)/amyotrophic lateral sclerosis (ALS). Multiple lines of evidence across diverse models suggest that functional loss of FUS can lead to neuronal dysfunction and/or neuronal cell death. Loss of FUS in the nucleus can impair alternative splicing and/or transcription, whereas dysfunction of FUS in the cytoplasm, especially in the dendritic spines of neurons, can cause mRNA destabilization...
2018: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/29772202/rnp-granule-assembly-via-ataxin-2-disordered-domains-is-required-for-long-term-memory-and-neurodegeneration
#2
Baskar Bakthavachalu, Joern Huelsmeier, Indulekha P Sudhakaran, Jens Hillebrand, Amanjot Singh, Arnas Petrauskas, Devasena Thiagarajan, M Sankaranarayanan, Laura Mizoue, Eric N Anderson, Udai Bhan Pandey, Eric Ross, K VijayRaghavan, Roy Parker, Mani Ramaswami
Human Ataxin-2 is implicated in the cause and progression of amyotrophic lateral sclerosis (ALS) and type 2 spinocerebellar ataxia (SCA-2). In Drosophila, a conserved atx2 gene is essential for animal survival as well as for normal RNP-granule assembly, translational control, and long-term habituation. Like its human homolog, Drosophila Ataxin-2 (Atx2) contains polyQ repeats and additional intrinsically disordered regions (IDRs). We demonstrate that Atx2 IDRs, which are capable of mediating liquid-liquid phase transitions in vitro, are essential for efficient formation of neuronal mRNP assemblies in vivo...
May 16, 2018: Neuron
https://www.readbyqxmd.com/read/29760288/-neuropathologic-subtypes-of-frontotemporal-lobar-degeneration
#3
Mari Tada, Akiyoshi Kakita
Frontotemporal lobar degeneration (FTLD) is a heterogeneous disease entity encompassing a wide variety of histopathological features and genetic backgrounds. The last two decades have seen the discovery of causative genes and the identification of relevant proteins. The current histopathological classification is based on the major types of protein deposition in the brain, and most FTLD cases can be placed into one of three pathological subgroups: FTLD-tau, FTLD-TDP, and FTLD-FUS. Further sub-classification within each subgroup is based on the morphology of neuronal and glial inclusions and lesion distribution...
May 2018: Brain and Nerve, Shinkei Kenkyū No Shinpo
https://www.readbyqxmd.com/read/29755516/synaptic-paths-to-neurodegeneration-the-emerging-role-of-tdp-43-and-fus-in-synaptic-functions
#4
REVIEW
Shuo-Chien Ling
TAR DNA-binding protein-43 KDa (TDP-43) and fused in sarcoma (FUS) as the defining pathological hallmarks for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coupled with ALS-FTD-causing mutations in both genes, indicate that their dysfunctions damage the motor system and cognition. On the molecular level, TDP-43 and FUS participate in the biogenesis and metabolism of coding and noncoding RNAs as well as in the transport and translation of mRNAs as part of cytoplasmic mRNA-ribonucleoprotein (mRNP) granules...
2018: Neural Plasticity
https://www.readbyqxmd.com/read/29728564/nuclear-egress-of-tdp-43-and-fus-occurs-independently-of-exportin-1-crm1
#5
Helena Ederle, Christina Funk, Claudia Abou-Ajram, Saskia Hutten, Eva B E Funk, Ralph H Kehlenbach, Susanne M Bailer, Dorothee Dormann
TDP-43 and FUS are nuclear proteins with multiple functions in mRNA processing. They play key roles in ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia), where they are partially lost from the nucleus and aggregate in the cytoplasm of neurons and glial cells. Defects in nucleocytoplasmic transport contribute to this pathology, hence nuclear import of both proteins has been studied in detail. However, their nuclear export routes remain poorly characterized and it is unclear whether aberrant nuclear export contributes to TDP-43 or FUS pathology...
May 4, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29723523/the-physiological-and-pathological-biophysics-of-phase-separation-and-gelation-of-rna-binding-proteins-in-amyotrophic-lateral-sclerosis-and-fronto-temporal-lobar-degeneration
#6
Peter St George-Hyslop, Julie Qiaojin Lin, Akinori Miyashita, Emma C Phillips, Seema Qamar, Suzanne J Randle, GuoZhen Wang
Many RNA binding proteins, including FUS, contain moderately repetitive, low complexity, intrinsically disordered domains. These sequence motifs have recently been found to underpin reversible liquid: liquid phase separation and gelation of these proteins, permitting them to reversibly transition from a monodispersed state to liquid droplet- or hydrogel-like states. This function allows the proteins to serve as scaffolds for the formation of reversible membraneless intracellular organelles such as nucleoli, stress granules and neuronal transport granules...
April 30, 2018: Brain Research
https://www.readbyqxmd.com/read/29677514/phase-separation-of-fus-is-suppressed-by-its-nuclear-import-receptor-and-arginine-methylation
#7
Mario Hofweber, Saskia Hutten, Benjamin Bourgeois, Emil Spreitzer, Annika Niedner-Boblenz, Martina Schifferer, Marc-David Ruepp, Mikael Simons, Dierk Niessing, Tobias Madl, Dorothee Dormann
Cytoplasmic FUS aggregates are a pathological hallmark in a subset of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). A key step that is disrupted in these patients is nuclear import of FUS mediated by the import receptor Transportin/Karyopherin-β2. In ALS-FUS patients, this is caused by mutations in the nuclear localization signal (NLS) of FUS that weaken Transportin binding. In FTD-FUS patients, Transportin is aggregated, and post-translational arginine methylation, which regulates the FUS-Transportin interaction, is lost...
April 19, 2018: Cell
https://www.readbyqxmd.com/read/29650794/comprehensive-analysis-of-the-mutation-spectrum-in-301-german-als-families
#8
Kathrin Müller, David Brenner, Patrick Weydt, Thomas Meyer, Torsten Grehl, Susanne Petri, Julian Grosskreutz, Joachim Schuster, Alexander E Volk, Guntram Borck, Christian Kubisch, Thomas Klopstock, Daniel Zeller, Sibylle Jablonka, Michael Sendtner, Stephan Klebe, Antje Knehr, Kornelia Günther, Joachim Weis, Kristl G Claeys, Berthold Schrank, Anne-Dorte Sperfeld, Annemarie Hübers, Markus Otto, Johannes Dorst, Thomas Meitinger, Tim M Strom, Peter M Andersen, Albert C Ludolph, Jochen H Weishaupt
OBJECTIVES: Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions. METHODS: Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS...
April 12, 2018: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/29625118/fus-causes-synaptic-hyperexcitability-in-drosophila-dendritic-arborization-neurons
#9
James B Machamer, Brian M Woolums, Gregory Fuller, Thomas E Lloyd
Mutations in the nuclear localization signal of the RNA binding protein FUS cause both Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). These mutations result in a loss of FUS from the nucleus and the formation of FUS-containing cytoplasmic aggregates in patients. To better understand the role of cytoplasmic FUS mislocalization in the pathogenesis of ALS, we identified a population of cholinergic neurons in Drosophila that recapitulate these pathologic hallmarks. Expression of mutant FUS or the Drosophila homolog, Cabeza (Caz), in class IV dendritic arborization neurons results in cytoplasmic mislocalization and axonal transport to presynaptic terminals...
April 3, 2018: Brain Research
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
#10
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/29557356/dna-plasticity-and-damage-in-amyotrophic-lateral-sclerosis
#11
REVIEW
Diane Penndorf, Otto W Witte, Alexandra Kretz
The pathophysiology of amyotrophic lateral sclerosis (ALS) is particularly challenging due to the heterogeneity of its clinical presentation and the diversity of cellular, molecular and genetic peculiarities involved. Molecular insights unveiled several novel genetic factors to be inherent in both familial and sporadic disease entities, whose characterizations in terms of phenotype prediction, pathophysiological impact and putative prognostic value are a topic of current researches. However, apart from genetically well-defined high-confidence and other susceptibility loci, the role of DNA damage and repair strategies of the genome as a whole, either elicited as a direct consequence of the underlying genetic mutation or seen as an autonomous parameter, in the initiation and progression of ALS, and the different cues involved in either process are still incompletely understood...
February 2018: Neural Regeneration Research
https://www.readbyqxmd.com/read/29547565/the-role-of-post-translational-modifications-on-prion-like-aggregation-and-liquid-phase-separation-of-fus
#12
REVIEW
Shannon N Rhoads, Zachary T Monahan, Debra S Yee, Frank P Shewmaker
Subcellular mislocalization and aggregation of the human FUS protein occurs in neurons of patients with subtypes of amyotrophic lateral sclerosis and frontotemporal dementia. FUS is one of several RNA-binding proteins that can functionally self-associate into distinct liquid-phase droplet structures. It is postulated that aberrant interactions within the dense phase-separated state can potentiate FUS's transition into solid prion-like aggregates that cause disease. FUS is post-translationally modified at numerous positions, which affect both its localization and aggregation propensity...
March 16, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29531866/overexpression-of-ter94-drosophila-vcp-improves-motor-neuron-degeneration-induced-by-knockdown-of-tbph-drosophila-tdp-43
#13
Yukie Kushimura, Takahiko Tokuda, Yumiko Azuma, Itaru Yamamoto, Ikuko Mizuta, Toshiki Mizuno, Masanori Nakagawa, Morio Ueyama, Yoshitaka Nagai, Hideki Yoshida, Masamitsu Yamaguchi
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by the motor neuron degeneration that eventually leads to complete paralysis and death within 2-5 years after disease onset. One of the major pathological hallmark of ALS is abnormal accumulation of inclusions containing TAR DNA-binding protein-43 (TDP-43). TDP-43 is normally found in the nucleus, but in ALS, it localizes in the cytoplasm as inclusions as well as in the nucleus. Loss of nuclear TDP-43 functions likely contributes to neurodegeneration...
2018: American Journal of Neurodegenerative Disease
https://www.readbyqxmd.com/read/29513014/rna-and-protein-interactors-with-tdp-43-in-human-spinal-cord-lysates-in-amyotrophic-lateral-sclerosis
#14
Kathryn Volkening, Brian A Keller, Cheryl Leystra-Lantz, Michael J Strong
The TAR DNA-binding protein of 43 kDa (TDP-43) is a dual function RNA- and DNA-binding protein with varied cellular functions. In degenerating motor neurons in amyotrophic lateral sclerosis (ALS), TDP-43 relocalizes from the nucleus to the cytosol, where it is sequestered into inclusions. It is likely that the pathogenic role of TDP-43 in ALS can involve either a gain or a loss of function, depending on the nature of its RNA or protein interactor. However, while TDP-43 binding partners have been identified in a range of model systems and from the human brain, interactors from human spinal-cord tissue have not...
April 6, 2018: Journal of Proteome Research
https://www.readbyqxmd.com/read/29499134/fus-regulates-activity-of-microrna-mediated-gene-silencing
#15
Tao Zhang, Yen-Ching Wu, Patrick Mullane, Yon Ju Ji, Honghe Liu, Lu He, Amit Arora, Ho-Yon Hwang, Amelia F Alessi, Amirhossein G Niaki, Goran Periz, Lin Guo, Hejia Wang, Elad Elkayam, Leemor Joshua-Tor, Sua Myong, John K Kim, James Shorter, Shao-En Ong, Anthony K L Leung, Jiou Wang
MicroRNA-mediated gene silencing is a fundamental mechanism in the regulation of gene expression. It remains unclear how the efficiency of RNA silencing could be influenced by RNA-binding proteins associated with the microRNA-induced silencing complex (miRISC). Here we report that fused in sarcoma (FUS), an RNA-binding protein linked to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), interacts with the core miRISC component AGO2 and is required for optimal microRNA-mediated gene silencing...
March 1, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29491392/disruption-of-er-mitochondria-signalling-in-fronto-temporal-dementia-and-related-amyotrophic-lateral-sclerosis
#16
REVIEW
Dawn H W Lau, Naomi Hartopp, Natalie J Welsh, Sarah Mueller, Elizabeth B Glennon, Gábor M Mórotz, Ambra Annibali, Patricia Gomez-Suaga, Radu Stoica, Sebastien Paillusson, Christopher C J Miller
Fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two related and incurable neurodegenerative diseases. Features of these diseases include pathological protein inclusions in affected neurons with TAR DNA-binding protein 43 (TDP-43), dipeptide repeat proteins derived from the C9ORF72 gene, and fused in sarcoma (FUS) representing major constituent proteins in these inclusions. Mutations in C9ORF72 and the genes encoding TDP-43 and FUS cause familial forms of FTD/ALS which provides evidence to link the pathology and genetics of these diseases...
February 28, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29472250/tau-protein-liquid-liquid-phase-separation-can-initiate-tau-aggregation
#17
Susanne Wegmann, Bahareh Eftekharzadeh, Katharina Tepper, Katarzyna M Zoltowska, Rachel E Bennett, Simon Dujardin, Pawel R Laskowski, Danny MacKenzie, Tarun Kamath, Caitlin Commins, Charles Vanderburg, Allyson D Roe, Zhanyun Fan, Amandine M Molliex, Amayra Hernandez-Vega, Daniel Muller, Anthony A Hyman, Eckhard Mandelkow, J Paul Taylor, Bradley T Hyman
The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid-liquid phase separation (LLPS) under cellular conditions and that phase-separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho-tau isolated from human Alzheimer brain...
April 3, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29458840/genome-wide-circulating-microrna-expression-profiling-reveals-potential-biomarkers-for-amyotrophic-lateral-sclerosis
#18
José Manuel Matamala, Raul Arias-Carrasco, Carolina Sanchez, Markus Uhrig, Leslie Bargsted, Soledad Matus, Vinicius Maracaja-Coutinho, Sebastian Abarzua, Brigitte van Zundert, Renato Verdugo, Patricio Manque, Claudio Hetz
The occurrence of mutations of TDP-43, FUS, and C9ORF72 in amyotrophic lateral sclerosis (ALS) suggests pathogenic alterations to RNA metabolism and specifically to microRNA (miRNA) biology. Moreover, several ALS-related proteins impact stress granule dynamics affecting miRNA biogenesis and cellular miRNA levels. miRNAs are present in different biological fluids and have been proposed as potential biomarkers. Here we used next-generation sequencing to perform a comparative analysis of the expression profile of circulating miRNAs in the serum of 2 mutant superoxide dismutase 1 transgenic mice...
April 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29449089/characterization-of-the-lncrna-transcriptome-in-mesc-derived-motor-neurons-implications-for-fus-als
#19
Silvia Biscarini, Davide Capauto, Giovanna Peruzzi, Lei Lu, Alessio Colantoni, Tiziana Santini, Neil A Shneider, Elisa Caffarelli, Pietro Laneve, Irene Bozzoni
Long non-coding RNAs (lncRNAs) are currently recognized as crucial players in nervous system development, function and pathology. In Amyotrophic Lateral Sclerosis (ALS), identification of causative mutations in FUS and TDP-43 or hexanucleotide repeat expansion in C9ORF72 point to the essential role of aberrant RNA metabolism in neurodegeneration. In this study, by taking advantage of an in vitro differentiation system generating mouse motor neurons (MNs) from embryonic stem cells, we identified and characterized the long non-coding transcriptome of MNs...
March 2018: Stem Cell Research
https://www.readbyqxmd.com/read/29434138/amyotrophic-lateral-sclerosis-after-receiving-the-human-papilloma-virus-vaccine-a-case-report-of-a-15-year-old-girl
#20
Ryota Hikiami, Hodaka Yamakado, Shinsui Tatsumi, Takashi Ayaki, Yuichiro Hashi, Hirofumi Yamashita, Nobukatsu Sawamoto, Teruyuki Tsuji, Makoto Urushitani, Ryosuke Takahashi
We herein report a 15-year-old girl who developed rapid progressive muscle weakness soon after the third injection of a bivalent human papilloma virus (HPV) vaccine. Although immunotherapies were performed for possible vaccine-related disorders, she died of respiratory failure 14 months after the onset of the disease. A genetic analysis identified a heterozygous p.P525L mutation of the fused in sarcoma (FUS) gene, and a histopathological analysis was also consistent with FUS-associated amyotrophic lateral sclerosis (ALS) without any evidence of neuroinflammation...
February 9, 2018: Internal Medicine
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