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FUS causes synaptic hyperexcitability in Drosophila dendritic arborization neurons.

FUS causes synaptic hyperexcitability in Drosophila dendritic arborization neurons. Brain Res. 2018 Apr 03;: Authors: Machamer JB, Woolums BM, Fuller G, Lloyd TE Abstract 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. Interestingly, overexpression of FUS or Caz causes the progressive loss of neuronal projections, reduction of synaptic mitochondria, and the appearance of large calcium transients within the synapse. Additionally, we find that overexpression of mutant but not wild type FUS results in a reduction in presynaptic Synaptotagmin, an integral component of the neurotransmitter release machinery, and mutant Caz specifically disrupts axonal transport and induces hyperexcitability. These results suggest that FUS/Caz overexpression disrupts neuronal function through multiple mechanisms, and that ALS-causing mutations impair t...
Source: Brain Research - Category: Neurology Authors: Tags: Brain Res Source Type: research

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Publication date: 19 April 2018 Source:Cell, Volume 173, Issue 3 Author(s): 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 loc...
Source: Cell - Category: Cytology Source Type: research
Amyotrophic lateral sclerosis (ALS) and the behavioural variant of frontotemporal dementia (bvFTD) commonly share the presence of TDP-43 inclusions. Structural MRI studies demonstrated evidence for TDP-43 pathology spread, but while structural imaging usually reveals overt neuronal loss, perfusion imaging may detect more subtle neural activity alterations. We evaluated perfusion as an early marker for incipient pathology associated brain alterations in TDP-43 proteinopathies. Cortical thickness (CT) and perfusion measurements were obtained in ALS (N=18), pathologically and/or genetically confirmed bvFTD-TDP (N=12), and hea...
Source: Neurobiology of Aging - Category: Neuroscience Authors: Source Type: research
Publication date: May 2018 Source:Neurochemistry International, Volume 115 Author(s): Zhihui Zhu, Georg Reiser Small heat shock proteins (sHsps) are a group of proteins with molecular mass between 12 and 43 kDa. Currently, 11 members of this family have been classified, namely HspB1 to HspB11. HspB1, HspB2, HspB5, HspB6, HspB7, and HspB8, which are expressed in brain have been observed to be related to the pathology of neurodegenerative diseases, including Parkinson's, Alzheimer's, Alexander's disease, multiple sclerosis, and human immunodeficiency virus-associated dementia. Specifically, sHsps interact with misfolding ...
Source: Neurochemistry International - Category: Neuroscience Source Type: research
(Washington University School of Medicine) Studying data from more than 125,000 individuals, an international team of researchers led by scientists at Washington University School of Medicine in St. Louis has identified genetic links between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The link between the seemingly unrelated disorders suggests that some drugs developed to treat ALS also may work against frontotemporal dementia and vice versa.
Source: EurekAlert! - Social and Behavioral Science - Category: International Medicine & Public Health Source Type: news
G4C2 repeat expansions within the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These bidirectionally transcribed expansions lead to (1) the accumulation of sense G4C2 and antisense G2C4 repeat-containing RNA, (2) the production of proteins of repeating dipeptides through unconventional translation of these transcripts, and (3) decreased C9ORF72 mRNA and protein expression. Consequently, there is ample opportunity for the C9ORF72 mutation to give rise to a spectrum of clinical manifestations, ranging from muscle weakness and atrophy to changes in be...
Source: Cold Spring Harbor perspectives in medicine - Category: Research Authors: Tags: Prion Diseases PERSPECTIVES Source Type: research
Publication date: Available online 28 March 2018 Source:Trends in Genetics Author(s): Hung Phuoc Nguyen, Christine Van Broeckhoven, Julie van der Zee Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease, characterized genetically by a disproportionately large contribution of rare genetic variation. Driven by advances in massive parallel sequencing and applied on large patient–control cohorts, systematic identification of these rare variants that make up the genetic architecture of ALS became feasible. In this review paper, we present a comprehensive overview of recently proposed ALS genes that ...
Source: Trends in Genetics - Category: Genetics & Stem Cells Source Type: research
Abstract Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease, characterized genetically by a disproportionately large contribution of rare genetic variation. Driven by advances in massive parallel sequencing and applied on large patient-control cohorts, systematic identification of these rare variants that make up the genetic architecture of ALS became feasible. In this review paper, we present a comprehensive overview of recently proposed ALS genes that were identified based on rare genetic variants (TBK1, CHCHD10, TUBA4A, CCNF, MATR3, NEK1, C21orf2, ANXA11, TIA1) and their potential releva...
Source: Trends in Genetics : TIG - Category: Genetics & Stem Cells Authors: Tags: Trends Genet Source Type: research
Publication date: Available online 26 March 2018 Source:The Lancet Neurology Author(s): 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, P...
Source: The Lancet Neurology - Category: Neurology Source Type: research
Mutations in the low complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1) was recently identified be associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in non-Hispanic white populations. We sequenced the TIA1 exons 11-13 encoding LCD in a series of 588 Chinese ALS/ALS-FTD patients (Familial ALS=29; Sporadic ALS=546; ALS-FTD=13) and 500 neurologically normal control subjects. We found a novel heterozygous missense mutation (c.973A>G, p.N325D) in a sporadic ALS patient, which suggest that TIA1 LCD mutations are not common in Chinese ALS/ALS-FTD.
Source: Neurobiology of Aging - Category: Neuroscience Authors: Source Type: research
AbstractPurpose of reviewMethods for the genetic diagnosis of neurodegenerative disorders were reviewed, including their backgrounds and applications in the laboratory. Majority of disease-causing gene mutations were uncommon in the general population, where dominant variations could be easily identified in certain disorders. The development of molecular, next generation sequencing (NGS) and cytogenetic techniques allowed to identify multiple genetic mutations leading to diseases. Using of the accurate multivariate diagnosis of diseases would be essential for appropriate treatment of patients, genetic counseling and preven...
Source: Molecular and Cellular Toxicology - Category: Cytology Source Type: research
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