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A Regulatory Circuitry Between Gria2, miR-409, and miR-495 Is Affected by ALS FUS Mutation in ESC-Derived Motor Neurons

AbstractMutations in fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (ALS). FUS is a multifunctional protein involved in the biogenesis and activity of several types of RNAs, and its role in the pathogenesis of ALS may involve both direct effects of disease-associated mutations through gain- and loss-of-function mechanisms and indirect effects due to the cross talk between different classes of FUS-dependent RNAs. To explore how FUS mutations impinge on motor neuron-specific RNA-based circuitries, we performed transcriptome profiling of small and long RNAs of motor neurons (MNs) derived from mouse embryonic stem cells carrying a FUS-P517L knock-in mutation, which is equivalent to human FUS-P525L, associated with a severe and juvenile-onset form of ALS. Combining ontological, predictive and molecular analyses, we found an inverse correlation between several classes of deregulated miRNAs and their corresponding mRNA targets in both homozygous and heterozygous P517L MNs. We validated a circuitry in which the upregulation of miR-409-3p and miR-495-3p, belonging to a brain-specific miRNA subcluster implicated in several neurodevelopmental disorders, produced the downregulation of Gria2, a subunit of the glutamate α‐amino‐3‐hydroxy‐5‐methyl-4-isoxazole propionic acid (AMPA) receptor with a significant role in excitatory neurotransmission. Moreover, we found that FUS was involved in mediating such miRNA repression. Gria2 alteration has been proposed to...
Source: Molecular Neurobiology - Category: Neurology Source Type: research

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Mutations in fused in sarcoma (FUS) are linked to amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease affecting both upper and lower motor neurons. While it is established that astrocytes contribute to the death of motor neurons in ALS, the specific contribution of mutant FUS (mutFUS) through astrocytes has not yet been studied. Here, we used primary astrocytes expressing a N‐terminally GFP tagged R521G mutant or wild‐type FUS (WTFUS) and show that mutFUS‐expressing astrocytes undergo astrogliosis, damage co‐cultured motor neurons via activation of an inflammatory response and produce conditioned...
Source: Glia - Category: Neurology Authors: Tags: RESEARCH ARTICLE Source Type: research
by Babykumari P. Chitramuthu, Denis G. Kay, Andrew Bateman, Hugh P. J. Bennett Progranulin (PGRN) is a glycoprotein with multiple roles in normal and disease states. Mutations within theGRN gene cause frontotemporal lobar degeneration (FTLD). The affected neurons display distinctive TAR DNA binding protein 43 (TDP-43) inclusions. How partial loss of PGRN causes TDP-43 neuropathology is poorly understood. TDP-43 inclusions are also found in affected neurons of patients with other neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In ALS, TDP-43 inclusions are typically also im...
Source: PLoS One - Category: Biomedical Science Authors: Source Type: research
RNAi of arcRNA hsrω affects sub-cellular localization of Drosophila FUS to drive neurodiseases. Exp Neurol. 2017 Mar 22;: Authors: Piccolo LL, Yamaguchi M Abstract Defective RNA metabolism is common pathogenic mechanisms involved in neurological disorders. Indeed, a conspicuous feature of some neurodegenerative diseases is the loss of nuclear activities of RNA-binding proteins (RBPs) like Fused in sarcoma (FUS) and eventually, their accumulation in cytoplasmic proteinaceous inclusions. Long non-coding RNAs (lncRNAs) are emerging as important regulators of tissue physiology and disease processes,...
Source: Experimental Neurology - Category: Neurology Authors: Tags: Exp Neurol Source Type: research
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)...
Source: Proceedings of the National Academy of Sciences - Category: Science Authors: Tags: PNAS Plus Source Type: research
Publication date: Available online 28 September 2016 Source:Progress in Neurobiology Author(s): Erika N. Guerrero, Haibo Wang, Joy Mitra, Pavana M. Hegde, Sara E. Stowell, Nicole F. Liachko, Brian C. Kraemer, Ralph M. Garruto, K.S. Rao, Muralidhar L. Hegde Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, f...
Source: Progress in Neurobiology - Category: Neuroscience Source Type: research
Fused in sarcoma (FUS) is a ubiquitously expressed RNA-binding protein proposed to function in various RNA metabolic pathways, including transcription regulation, pre-mRNA splicing, RNA transport and microRNA processing. Mutations in the FUS gene were identified in patients with amyotrophic lateral sclerosis (ALS), but the pathomechanisms by which these mutations cause ALS are not known. Here, we show that FUS interacts with the minor spliceosome constituent U11 snRNP, binds preferentially to minor introns and directly regulates their removal. Furthermore, a FUS knockout in neuroblastoma cells strongly disturbs the splicin...
Source: EMBO Journal - Category: Molecular Biology Authors: Tags: Neuroscience, RNA Biology Articles Source Type: research
In this study, we generated induced pluripotent stem cells (iPSC) from two familial ALS (FALS) patients with a missense mutation in the fused-in sarcoma (FUS) gene carrying the heterozygous FUS H517D mutation, and isogenic iPSCs with the homozygous FUS H517D mutation by genome editing technology. These cell-derived motor neurons mimicked several neurodegenerative phenotypes including mis-localization of FUS into cytosolic and stress granules under stress conditions, and cellular vulnerability. Moreover, exon array analysis using motor neuron precursor cells (MPCs) combined with CLIP-seq datasets revealed aberrant gene expr...
Source: Stem Cell Reports - Category: Stem Cells Source Type: research
In this study, we generated induced pluripotent stem cells (iPSC) from two familial ALS (FALS) patients with a missense mutation in the fused-in sarcoma (FUS) gene carrying the heterozygous FUS H517D mutation, and the isogenic iPSCs with the homozygous FUS H517D mutation obtained by genome editing from the healthy control iPSCs. These cell-derived motor neurons mimicked several neurodegenerative phenotypes. A part of the mutant FUS protein was localized outside the nucleus and co-localized with stress granules under stress conditions. Moreover, FALS motor neurons showed more apoptotic activity than did control motor neuron...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by array Homo sapiens Source Type: research
This study identified a heterozygous de novo variant of unknown clinical significance (VUS) in the fused in sarcoma (FUS) gene [c.1554_1557del]. Although initially reported as a VUS, the clinical data from our patient and data from the medical literature support that the variant is indeed disease causing. Discussion The genetic etiology of amyotrophic lateral sclerosis (ALS) is heterogeneous, and as clinical sequencing for FUS was not available, WES was the only method by which a diagnosis of juvenile ALS could be made. This article is protected by copyright. All rights reserved.
Source: Muscle and Nerve - Category: Internal Medicine Authors: Tags: Case of the Month Source Type: research
This article is protected by copyright. All rights reserved.
Source: Brain Pathology - Category: Neurology Authors: Tags: Mini ‐Symposium Source Type: research
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