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3 results on '"Scekic-Zahirovic, Jelena"'

1. Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss

Author

Scekic-Zahirovic, Jelena, Sendscheid, Oliver, El Oussini, Hajer, Jambeau, Mélanie, Sun, Ying, Mersmann, Sina, Wagner, Marina, Dieterlé, Stéphane, Sinniger, Jérome, Dirrig-Grosch, Sylvie, Drenner, Kevin, Birling, Marie-Christine, Qiu, Jinsong, Zhou, Yu, Li, Hairi, Fu, Xiang-Dong, Rouaux, Caroline, Shelkovnikova, Tatyana, Witting, Anke, Ludolph, Albert C, Kiefer, Friedemann, Storkebaum, Erik, Lagier-Tourenne, Clotilde, and Dupuis, Luc

Subjects
Neurosciences, Brain Disorders, Genetics, Dementia, Neurodegenerative, Rare Diseases, Acquired Cognitive Impairment, ALS, 2.1 Biological and endogenous factors, Aetiology, Neurological, Animals, Brain, Cytoplasm, Mice, Inbred C57BL, Mice, Transgenic, Motor Neurons, Mutation, RNA-Binding Protein FUS, Spinal Cord, amyotrophic lateral sclerosis, frontotemporal dementia, FUS, motor neuron degeneration, PY-NLS, PY‐NLS, Biological Sciences, Information and Computing Sciences, Medical and Health Sciences, Developmental Biology
Abstract

FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons.

Published
2016

2. Conditional truncation of the FUS protein in mice : a new animal model of the ALS/FTD continuum

Author

Scekic-Zahirovic, Jelena, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg, Universität Basel, Université de Fribourg (Fribourg, Suisse), Luc Dupuis, Marlene Bartos, Pico Caroni, and STAR, ABES

Subjects
Cytoplasmic mislocalization, SLA/DFT, Cytoplasmique localisation, ALS/FTLD, Toxic gain of function, Gain de fonction, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], FUS
Abstract

Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTLD) are now considered as a unique clinicopathological spectrum referred to as ALS/FTLD. Cytoplasmic aggregation of the physiologically nuclear FUS protein is a hallmark feature of a subset of ALS/FTLD. It remains unknonwn whether the critical pathogenic event relies on a loss of FUS normal nuclear functions, a toxic gain of function of FUS in the cytoplasm, or a combination of both.To answer this question we have generated a conditional mouse model expressing truncated FUS without nuclear localization signal - FusΔNLS. Our data showed that complete cytoplasmic mislocalization of truncated FUS protein within spinal motor neurons is a major determinant of motor neuron degeneration via toxic gain of function. A partial mislocalization of truncated FUS protein was sufficient to trigger key features of ALS and of FTLD.These studies allowed the elucidation of mechanisms underlying FUS role in ALS/FTLD, and will hopefully lead to development of therapies for these devastating diseases., La sclérose latérale amyotrophique (SLA) et la démence fronto-temporale (DFT) sont deux maladies qui constituent un continuum clinico-pathologique. La mutation de FUS, une protéine nucléaire à fonctions multiples, provoque des cas familaux de SLA, et ces mutations provoquent une redistribution sub-cellulaire de FUS, du noyau vers le cytoplasme. Certains cas de DFT présentent une telles distribution anormale en l’absence de mutations de FUS. Il n’est pas connu si la maladie est provoquée par une perte de la fonction nucléaire de FUS et/ou un gain de fonction cytoplasmique.Nous avons généré et caractérisé une lignée de souris exprimant une forme cytoplasmique de FUS (Fus-ΔNLS). La localisation exclusive de FUS dans le cytoplasme provoque la mort des motoneurones via un gain de fonction dans les motoneurones eux-mêmes. Une localisation cytoplasmique partielle de FUS est suffisante pour développer un phénotype de la SLA et de DFT. Les mécanismes élucidés permettront de comprendre les bases des SLA/DFT.

Published
2016

3. Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss

Author

Scekic‐Zahirovic, Jelena, Sendscheid, Oliver, El Oussini, Hajer, Jambeau, Mélanie, Sun, Ying, Mersmann, Sina, Wagner, Marina, Dieterlé, Stéphane, Sinniger, Jérome, Dirrig‐Grosch, Sylvie, Drenner, Kevin, Birling, Marie‐Christine, Qiu, Jinsong, Zhou, Yu, Li, Hairi, Fu, Xiang‐Dong, Rouaux, Caroline, Shelkovnikova, Tatyana, Witting, Anke, Ludolph, Albert C, Kiefer, Friedemann, Storkebaum, Erik, Lagier‐Tourenne, Clotilde, and Dupuis, Luc

Subjects
Article, amyotrophic lateral sclerosis, frontotemporal dementia, FUS, motor neuron degeneration, PY‐NLS, Molecular Biology of Disease, Neuroscience
Abstract

FUS is an RNA‐binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS‐containing aggregates are often associated with concomitant loss of nuclear FUS. Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell‐specific CRE‐mediated expression of wild‐type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons.

Published
2016
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