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Viral Infections Exacerbate FUS-ALS Phenotypes in iPSC-Derived Spinal Neurons in a Virus Species-Specific Manner

Amyotrophic lateral sclerosis (ALS) arises from an interplay of genetic mutations and environmental factors. ssRNA viruses are possible ALS risk factors, but testing their interaction with mutations such as in FUS, which encodes an RNA-binding protein, has been difficult due to the lack of a human d...

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Autores principales: Bellmann, Jessica, Monette, Anne, Tripathy, Vadreenath, Sójka, Anna, Abo-Rady, Masin, Janosh, Antje, Bhatnagar, Rajat, Bickle, Marc, Mouland, Andrew J., Sterneckert, Jared
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817715/
https://www.ncbi.nlm.nih.gov/pubmed/31695598
http://dx.doi.org/10.3389/fncel.2019.00480
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author Bellmann, Jessica
Monette, Anne
Tripathy, Vadreenath
Sójka, Anna
Abo-Rady, Masin
Janosh, Antje
Bhatnagar, Rajat
Bickle, Marc
Mouland, Andrew J.
Sterneckert, Jared
author_facet Bellmann, Jessica
Monette, Anne
Tripathy, Vadreenath
Sójka, Anna
Abo-Rady, Masin
Janosh, Antje
Bhatnagar, Rajat
Bickle, Marc
Mouland, Andrew J.
Sterneckert, Jared
author_sort Bellmann, Jessica
collection PubMed
description Amyotrophic lateral sclerosis (ALS) arises from an interplay of genetic mutations and environmental factors. ssRNA viruses are possible ALS risk factors, but testing their interaction with mutations such as in FUS, which encodes an RNA-binding protein, has been difficult due to the lack of a human disease model. Here, we use isogenic induced pluripotent stem cell (iPSC)-derived spinal neurons (SNs) to investigate the interaction between ssRNA viruses and mutant FUS. We find that rabies virus (RABV) spreads ALS phenotypes, including the formation of stress granules (SGs) with aberrant composition due to increased levels of FUS protein, as well as neurodegeneration and reduced restriction activity by FUS mutations. Consistent with this, iPSC-derived SNs harboring mutant FUS are more sensitive to human immunodeficiency virus (HIV-1) and Zika viruses (ZIKV). We demonstrate that RABV and HIV-1 exacerbate cytoplasmic mislocalization of FUS. Our results demonstrate that viral infections worsen ALS pathology in SNs with genetic risk factors, suggesting a novel role for viruses in modulating patient phenotypes.
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spelling pubmed-68177152019-11-06 Viral Infections Exacerbate FUS-ALS Phenotypes in iPSC-Derived Spinal Neurons in a Virus Species-Specific Manner Bellmann, Jessica Monette, Anne Tripathy, Vadreenath Sójka, Anna Abo-Rady, Masin Janosh, Antje Bhatnagar, Rajat Bickle, Marc Mouland, Andrew J. Sterneckert, Jared Front Cell Neurosci Neuroscience Amyotrophic lateral sclerosis (ALS) arises from an interplay of genetic mutations and environmental factors. ssRNA viruses are possible ALS risk factors, but testing their interaction with mutations such as in FUS, which encodes an RNA-binding protein, has been difficult due to the lack of a human disease model. Here, we use isogenic induced pluripotent stem cell (iPSC)-derived spinal neurons (SNs) to investigate the interaction between ssRNA viruses and mutant FUS. We find that rabies virus (RABV) spreads ALS phenotypes, including the formation of stress granules (SGs) with aberrant composition due to increased levels of FUS protein, as well as neurodegeneration and reduced restriction activity by FUS mutations. Consistent with this, iPSC-derived SNs harboring mutant FUS are more sensitive to human immunodeficiency virus (HIV-1) and Zika viruses (ZIKV). We demonstrate that RABV and HIV-1 exacerbate cytoplasmic mislocalization of FUS. Our results demonstrate that viral infections worsen ALS pathology in SNs with genetic risk factors, suggesting a novel role for viruses in modulating patient phenotypes. Frontiers Media S.A. 2019-10-22 /pmc/articles/PMC6817715/ /pubmed/31695598 http://dx.doi.org/10.3389/fncel.2019.00480 Text en Copyright © 2019 Bellmann, Monette, Tripathy, Sójka, Abo-Rady, Janosh, Bhatnagar, Bickle, Mouland and Sterneckert. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Bellmann, Jessica
Monette, Anne
Tripathy, Vadreenath
Sójka, Anna
Abo-Rady, Masin
Janosh, Antje
Bhatnagar, Rajat
Bickle, Marc
Mouland, Andrew J.
Sterneckert, Jared
Viral Infections Exacerbate FUS-ALS Phenotypes in iPSC-Derived Spinal Neurons in a Virus Species-Specific Manner
title Viral Infections Exacerbate FUS-ALS Phenotypes in iPSC-Derived Spinal Neurons in a Virus Species-Specific Manner
title_full Viral Infections Exacerbate FUS-ALS Phenotypes in iPSC-Derived Spinal Neurons in a Virus Species-Specific Manner
title_fullStr Viral Infections Exacerbate FUS-ALS Phenotypes in iPSC-Derived Spinal Neurons in a Virus Species-Specific Manner
title_full_unstemmed Viral Infections Exacerbate FUS-ALS Phenotypes in iPSC-Derived Spinal Neurons in a Virus Species-Specific Manner
title_short Viral Infections Exacerbate FUS-ALS Phenotypes in iPSC-Derived Spinal Neurons in a Virus Species-Specific Manner
title_sort viral infections exacerbate fus-als phenotypes in ipsc-derived spinal neurons in a virus species-specific manner
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817715/
https://www.ncbi.nlm.nih.gov/pubmed/31695598
http://dx.doi.org/10.3389/fncel.2019.00480
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