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https://www.readbyqxmd.com/read/28100023/frontotemporal-lobar-degeneration-pathogenesis-pathology-and-pathways-to-phenotype
#1
REVIEW
David Ma Mann, Julie S Snowden
Frontotemporal Lobar Degeneration (FTLD) is a clinically, pathologically and genetically heterogeneous group of disorders that affect principally the frontal and temporal lobes of the brain. There are three major associated clinical syndromes, behavioural variant frontotemporal dementia (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA); three principal histologies, involving tau, TDP-43 and FUS proteins; and mutations in three major genes, MAPT, GRN and C9orf72, along with several other less common gene mutations...
January 18, 2017: Brain Pathology
https://www.readbyqxmd.com/read/28096243/fused-in-sarcoma-neuropathology-in-neurodegenerative-disease
#2
Ian R A Mackenzie, Manuela Neumann
Abnormal intracellular accumulation of the fused in sarcoma (FUS) protein is the characteristic pathological feature of cases of familial amyotrophic lateral sclerosis (ALS) caused by FUS mutations (ALS-FUS) and several uncommon disorders that may present with sporadic frontotemporal dementia (FTLD-FUS). Although these findings provide further support for the concept that ALS and FTD are closely related clinical syndromes with an overlapping molecular basis, important differences in the pathological features and results from experimental models indicate that ALS-FUS and FTLD-FUS have distinct pathogenic mechanisms...
January 17, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28094300/sequestration-of-prmt1-and-nd1-l-mrna-into-als-linked-fus-mutant-r521c-positive-aggregates-contributes-to-neurite-degeneration-upon-oxidative-stress
#3
Mi-Hee Jun, Hyun-Hee Ryu, Yong-Woo Jun, Tongtong Liu, Yan Li, Chae-Seok Lim, Yong-Seok Lee, Bong-Kiun Kaang, Deok-Jin Jang, Jin-A Lee
Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, are associated with familial amyotrophic lateral sclerosis (ALS). However, little is known about how ALS-causing mutations alter protein-protein and protein-RNA complexes and contribute to neurodegeneration. In this study, we identified protein arginine methyltransferase 1 (PRMT1) as a protein that more avidly associates with ALS-linked FUS-R521C than with FUS-WT (wild type) or FUS-P525L using co-immunoprecipitation and LC-MS analysis. Abnormal association between FUS-R521C and PRMT1 requires RNA, but not methyltransferase activity...
January 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28072389/suppression-of-c9orf72-rna-repeat-induced-neurotoxicity-by-the-als-associated-rna-binding-protein-zfp106
#4
Barbara Celona, John von Dollen, Sarat C Vatsavayai, Risa Kashima, Jeffrey R Johnson, Amy A Tang, Akiko Hata, Bruce L Miller, Eric J Huang, Nevan J Krogan, William W Seeley, Brian L Black
Expanded GGGGCC repeats in the first intron of the C9orf72 gene represent the most common cause of familial amyotrophic lateral sclerosis (ALS), but the mechanisms underlying repeat-induced disease remain incompletely resolved. One proposed gain-of-function mechanism is that repeat-containing RNA forms aggregates that sequester RNA binding proteins, leading to altered RNA metabolism in motor neurons. Here, we identify the zinc finger protein Zfp106 as a specific GGGGCC RNA repeat-binding protein, and using affinity purification-mass spectrometry, we show that Zfp106 interacts with multiple other RNA binding proteins, including the ALS-associated factors TDP-43 and FUS...
January 10, 2017: ELife
https://www.readbyqxmd.com/read/28057713/genetic-epidemiology-of-amyotrophic-lateral-sclerosis-a-systematic-review-and-meta-analysis
#5
Zhang-Yu Zou, Zhi-Rui Zhou, Chun-Hui Che, Chang-Yun Liu, Rao-Li He, Hua-Pin Huang
BACKGROUND: Genetic studies have shown that C9orf72, SOD1, TARDBP and FUS are the most common mutated genes in amyotrophic lateral sclerosis (ALS). Here, we performed a meta-analysis to determine the mutation frequencies of these major ALS-related genes in patients with ALS. METHODS: We performed an extensive literature research to identify all original articles reporting frequencies of C9orf72, SOD1, TARDBP and FUS mutations in ALS. The mutation frequency and effect size of each study were combined...
January 5, 2017: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/28057298/amyotrophic-lateral-sclerosis-pathogenesis-converges-on-defects-in-protein-homeostasis-associated-with-tdp-43-mislocalization-and-proteasome-mediated-degradation-overload
#6
G Lin, D Mao, H J Bellen
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects upper and/or lower motor neurons. It usually affects people between the ages of 40-70. The average life expectancy is about 3-5 years after diagnosis and there is no effective cure available. Identification of variants in more than 20 different loci has provided insight into the pathogenic molecular mechanisms mediating disease pathogenesis. In this review, we focus on seven ALS-causing genes: TDP-43, FUS, C9orf72, VCP, UBQLN2, VAPB and SOD-1, which encompass about 90% of the variants causing familial ALS...
2017: Current Topics in Developmental Biology
https://www.readbyqxmd.com/read/28054830/a-novel-mutation-of-the-c-terminal-amino-acid-of-fus-y526c-strengthens-fus-gene-as-the-most-frequent-genetic-factor-in-aggressive-juvenile-als
#7
Philippe Corcia, Veronique Danel, Arnaud Lacour, Stephane Beltran, Christian Andres, Philippe Couratier, Helene Blasco, Patrick Vourc'h
Although amyotrophic lateral sclerosis (ALS) typically occurs around 60 years, numerous publications report an onset of ALS before the age of 25 years that define juvenile ALS (jALS). Over the last decade, growing literature mentioned jALS with an aggressive evolution which are mainly linked to the FUS gene. We report here the case of a 25-year-old woman with a bulbar onset ALS that progressed in less than 12 months to invasive ventilation due to respiratory failure; Genetic screening identified a new mutation in the FUS gene that lies within the last codon...
January 5, 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/28054357/linking-amyotrophic-lateral-sclerosis-and-spinal-muscular-atrophy-through-rna-transcriptome-homeostasis-a-genomics-perspective
#8
REVIEW
Margarida Gama-Carvalho, Marina L Garcia-Vaquero, Francisco R Pinto, Florence Besse, Joachim Weis, Aaron Voigt, Jörg B Schulz, Javier De Las Rivas
In this review we present our most recent understanding of key biomolecular processes that underlie two motor neuron degenerative disorders, Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA). We focus on the role of four multifunctional proteins involved in RNA metabolism (TDP-43, FUS, SMN and Senataxin) that play a causal role in these diseases. Recent results have led to a novel scenario of intricate connections between these four proteins, bringing transcriptome homeostasis into the spotlight as a common theme in motor neuron degeneration...
January 5, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27999880/-pathomechanisms-and-clinical-aspects-of-frontotemporal-lobar-degeneration
#9
REVIEW
K Bürger, T Arzberger, J Stephan, J Levin, D Edbauer
BACKGROUND: Frontotemporal lobar degeneration (FTLD) includes a spectrum of heterogeneous clinical and neuropathological diseases. In a strict sense this includes the behavioral variant of frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA) and both variants can be associated with amyotrophic lateral sclerosis (FTD-ALS). In a broader sense FTLD also includes progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). In recent years the strong genetic component of FTLD has become increasingly clear...
December 20, 2016: Der Nervenarzt
https://www.readbyqxmd.com/read/27978769/genetic-analysis-of-patients-with-familial-and-sporadic-amyotrophic-lateral-sclerosis-in-a-brazilian-research-center
#10
Gerson Chadi, Jessica Ruivo Maximino, Frederico Mennucci de Haidar Jorge, FabríCIO Castro dE Borba, Joyce Meire Gilio, Dagoberto Callegaro, Camila GalvãO Lopes, Samantha Nakamura Dos Santos, Gabriela Natania Sales Rebelo
OBJECTIVE: To investigate gene mutations in familial form (FALS) and sporadic form (SALS) of amyotrophic lateral sclerosis (ALS) in a highly miscegenated population. METHODS: Frequencies of mutations in the C9orfF72, TARDBP, SOD1, FUS and VAPB genes were investigated in a cohort of FALS (n = 39) and SALS (n = 189) subjects from the Research Centre of the University of São Paulo School of Medicine. All patients were subjected to C9orf72 and TARDBP analyses...
December 15, 2016: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/27942908/could-sirtuin-activities-modify-als-onset-and-progression
#11
REVIEW
Bor Luen Tang
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a complex etiology. Sirtuins have been implicated as disease-modifying factors in several neurological disorders, and in the past decade, attempts have been made to check if manipulating Sirtuin activities and levels could confer benefit in terms of neuroprotection and survival in ALS models. The efforts have largely focused on mutant SOD1, and while limited in scope, the results were largely positive. Here, the body of work linking Sirtuins with ALS is reviewed, with discussions on how Sirtuins and their activities may impact on the major etiological mechanisms of ALS...
December 10, 2016: Cellular and Molecular Neurobiology
https://www.readbyqxmd.com/read/27930290/gamma-motor-neurons-survive-and-exacerbate-alpha-motor-neuron-degeneration-in-als
#12
Melanie Lalancette-Hebert, Aarti Sharma, Alexander K Lyashchenko, Neil A Shneider
The molecular and cellular basis of selective motor neuron (MN) vulnerability in amyotrophic lateral sclerosis (ALS) is not known. In genetically distinct mouse models of familial ALS expressing mutant superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS), we demonstrate selective degeneration of alpha MNs (α-MNs) and complete sparing of gamma MNs (γ-MNs), which selectively innervate muscle spindles. Resistant γ-MNs are distinct from vulnerable α-MNs in that they lack synaptic contacts from primary afferent (IA) fibers...
December 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27920024/biology-and-pathobiology-of-tdp-43-and-emergent-therapeutic-strategies
#13
Lin Guo, James Shorter
Cytoplasmic TDP-43 mislocalization and aggregation is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 is an RNA-binding protein (RBP) with a prion-like domain (PrLD) that promotes TDP-43 misfolding. PrLDs possess compositional similarity to canonical prion domains of various yeast proteins, including Sup35. Strikingly, disease-causing TDP-43 mutations reside almost exclusively in the PrLD and can enhance TDP-43 misfolding and toxicity. Another ∼70 human RBPs harbor PrLDs, including FUS, TAF15, EWSR1, hnRNPA1, and hnRNPA2, which have surfaced in the etiology of neurodegenerative diseases...
December 5, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/27906075/nuclear-bodies-reorganize-during-myogenesis-in-vitro-and-are-differentially-disrupted-by-expression-of-fshd-associated-dux4
#14
Sachiko Homma, Mary Lou Beermann, Bryant Yu, Frederick M Boyce, Jeffrey Boone Miller
BACKGROUND: Nuclear bodies, such as nucleoli, PML bodies, and SC35 speckles, are dynamic sub-nuclear structures that regulate multiple genetic and epigenetic processes. Additional regulation is provided by RNA/DNA handling proteins, notably TDP-43 and FUS, which have been linked to ALS pathology. Previous work showed that mouse cell line myotubes have fewer but larger nucleoli than myoblasts, and we had found that nuclear aggregation of TDP-43 in human myotubes was induced by expression of DUX4-FL, a transcription factor that is aberrantly expressed and causes pathology in facioscapulohumeral dystrophy (FSHD)...
December 1, 2016: Skeletal Muscle
https://www.readbyqxmd.com/read/27898262/characterization-of-genetic-loss-of-function-of-fus-in-zebrafish
#15
Svetlana Lebedeva, António M de Jesus Domingues, Falk Butter, René F Ketting
The RNA-binding protein FUS is implicated in transcription, alternative splicing of neuronal genes and DNA repair. Mutations in FUS have been linked to human neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis). We genetically disrupted fus in zebrafish (Danio rerio) using the CRISPR-Cas9 system. The fus knockout animals are fertile and did not show any distinctive phenotype. Mutation of fus induces mild changes in gene expression on the transcriptome and proteome level in the adult brain...
January 2, 2017: RNA Biology
https://www.readbyqxmd.com/read/27849576/two-familial-als-proteins-function-in-prevention-repair-of-transcription-associated-dna-damage
#16
Sarah J Hill, Daniel A Mordes, Lisa A Cameron, Donna S Neuberg, Serena Landini, Kevin Eggan, David M Livingston
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27818323/als-causing-mutations-differentially-affect-pgc-1%C3%AE-expression-and-function-in-the-brain-vs-peripheral-tissues
#17
Hanna Bayer, Kerstin Lang, Eva Buck, Julia Higelin, Lara Barteczko, Noemi Pasquarelli, Jasmin Sprissler, Tanja Lucas, Karlheinz Holzmann, Maria Demestre, Katrin S Lindenberg, Karin M Danzer, Tobias Boeckers, Albert C Ludolph, Luc Dupuis, Patrick Weydt, Anke Witting
BACKGROUND: Monogenetic forms of amyotrophic lateral sclerosis (ALS) offer an opportunity for unraveling the molecular mechanisms underlying this devastating neurodegenerative disorder. In order to identify a link between ALS-related metabolic changes and neurodegeneration, we investigated whether ALS-causing mutations interfere with the peripheral and brain-specific expression and signaling of the metabolic master regulator PGC (PPAR gamma coactivator)-1α (PGC-1α). METHODS: We analyzed the expression of PGC-1α isoforms and target genes in two mouse models of familial ALS and validated the stimulated PGC-1α signaling in primary adipocytes and neurons of these animal models and in iPS derived motoneurons of two ALS patients harboring two different frame-shift FUS/TLS mutations...
January 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/27810362/imbalance-of-mitochondrial-dynamics-in-drosophila-models-of-amyotrophic-lateral-sclerosis
#18
Volodya Altanbyek, Sun-Joo Cha, Ga-Un Kang, Dai Sig Im, Seongsoo Lee, Hyung-Jun Kim, Kiyoung Kim
Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease, characterized by progressive and selective loss of motor neurons in the brain and spinal cord. DNA/RNA-binding proteins such as TDP-43, FUS, and TAF15 have been linked with the sporadic and familial forms of ALS. However, the exact pathogenic mechanism of ALS is still unknown. Recently, we found that ALS-causing genes such as TDP-43, FUS, and TAF15 genetically interact with mitochondrial dynamics regulatory genes. In this study, we show that mitochondrial fission was highly enhanced in muscles and motor neurons of TDP-43, FUS, and TAF15-induced fly models of ALS...
October 31, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27796305/monitoring-peripheral-nerve-degeneration-in-als-by-label-free-stimulated-raman-scattering-imaging
#19
Feng Tian, Wenlong Yang, Daniel A Mordes, Jin-Yuan Wang, Johnny S Salameh, Joanie Mok, Jeannie Chew, Aarti Sharma, Ester Leno-Duran, Satomi Suzuki-Uematsu, Naoki Suzuki, Steve S Han, Fa-Ke Lu, Minbiao Ji, Rosanna Zhang, Yue Liu, Jack Strominger, Neil A Shneider, Leonard Petrucelli, X Sunney Xie, Kevin Eggan
The study of amyotrophic lateral sclerosis (ALS) and potential interventions would be facilitated if motor axon degeneration could be more readily visualized. Here we demonstrate that stimulated Raman scattering (SRS) microscopy could be used to sensitively monitor peripheral nerve degeneration in ALS mouse models and ALS autopsy materials. Three-dimensional imaging of pre-symptomatic SOD1 mouse models and data processing by a correlation-based algorithm revealed that significant degeneration of peripheral nerves could be detected coincidentally with the earliest detectable signs of muscle denervation and preceded physiologically measurable motor function decline...
October 31, 2016: Nature Communications
https://www.readbyqxmd.com/read/27794540/pink1-and-parkin-are-genetic-modifiers-for-fus-induced-neurodegeneration
#20
Yanbo Chen, Jianwen Deng, Peng Wang, Mengxue Yang, Xiaoping Chen, Li Zhu, Jianghong Liu, Bingwei Lu, Yan Shen, Kazuo Fushimi, Qi Xu, Jane Y Wu
Dysregulation of Fused in Sarcoma (FUS) gene expression is associated with fronto-temporal lobar degeneration (FTLD), and missense mutations in the FUS gene have been identified in patients affected by amyotrophic lateral sclerosis (ALS). However, molecular and cellular defects underlying FUS proteinopathy remain to be elucidated. Here, we examined whether genes important for mitochondrial quality control play a role in FUS proteinopathy. In our genetic screening, Pink1 and Park genes were identified as modifiers of neurodegeneration phenotypes induced by wild type (Wt) or ALS-associated P525L-mutant human FUS...
October 29, 2016: Human Molecular Genetics
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