ALS mutant FUS proteins are recruited into stress granules in induced pluripotent stem cell-derived motoneurons

Patient-derived induced pluripotent stem cells (iPSCs) provide an opportunity to study human diseases mainly in those cases for which no suitable model systems are available. Here, we have taken advantage of in vitro iPSCs derived from patients affected by amyotrophic lateral sclerosis (ALS) and car...

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Main Authors:	Lenzi, Jessica, De Santis, Riccardo, de Turris, Valeria, Morlando, Mariangela, Laneve, Pietro, Calvo, Andrea, Caliendo, Virginia, Chiò, Adriano, Rosa, Alessandro, Bozzoni, Irene
Format:	Online
Language:	English
Published:	The Company of Biologists 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486861/

id	pubmed-4486861
recordtype	oai_dc
spelling	pubmed-44868612015-07-10 ALS mutant FUS proteins are recruited into stress granules in induced pluripotent stem cell-derived motoneurons Lenzi, Jessica De Santis, Riccardo de Turris, Valeria Morlando, Mariangela Laneve, Pietro Calvo, Andrea Caliendo, Virginia Chiò, Adriano Rosa, Alessandro Bozzoni, Irene Resource Article Patient-derived induced pluripotent stem cells (iPSCs) provide an opportunity to study human diseases mainly in those cases for which no suitable model systems are available. Here, we have taken advantage of in vitro iPSCs derived from patients affected by amyotrophic lateral sclerosis (ALS) and carrying mutations in the RNA-binding protein FUS to study the cellular behavior of the mutant proteins in the appropriate genetic background. Moreover, the ability to differentiate iPSCs into spinal cord neural cells provides an in vitro model mimicking the physiological conditions. iPSCs were derived from FUSR514S and FUSR521C patient fibroblasts, whereas in the case of the severe FUSP525L mutation, in which fibroblasts were not available, a heterozygous and a homozygous iPSC line were raised by TALEN-directed mutagenesis. We show that aberrant localization and recruitment of FUS into stress granules (SGs) is a prerogative of the FUS mutant proteins and occurs only upon induction of stress in both undifferentiated iPSCs and spinal cord neural cells. Moreover, we show that the incorporation into SGs is proportional to the amount of cytoplasmic FUS, strongly correlating with the cytoplasmic delocalization phenotype of the different mutants. Therefore, the available iPSCs represent a very powerful system for understanding the correlation between FUS mutations, the molecular mechanisms of SG formation and ALS ethiopathogenesis. The Company of Biologists 2015-07-01 /pmc/articles/PMC4486861/ /pubmed/26035390 http://dx.doi.org/10.1242/dmm.020099 Text en © 2015. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Lenzi, Jessica De Santis, Riccardo de Turris, Valeria Morlando, Mariangela Laneve, Pietro Calvo, Andrea Caliendo, Virginia Chiò, Adriano Rosa, Alessandro Bozzoni, Irene
spellingShingle	Lenzi, Jessica De Santis, Riccardo de Turris, Valeria Morlando, Mariangela Laneve, Pietro Calvo, Andrea Caliendo, Virginia Chiò, Adriano Rosa, Alessandro Bozzoni, Irene ALS mutant FUS proteins are recruited into stress granules in induced pluripotent stem cell-derived motoneurons
author_facet	Lenzi, Jessica De Santis, Riccardo de Turris, Valeria Morlando, Mariangela Laneve, Pietro Calvo, Andrea Caliendo, Virginia Chiò, Adriano Rosa, Alessandro Bozzoni, Irene
author_sort	Lenzi, Jessica
title	ALS mutant FUS proteins are recruited into stress granules in induced pluripotent stem cell-derived motoneurons
title_short	ALS mutant FUS proteins are recruited into stress granules in induced pluripotent stem cell-derived motoneurons
title_full	ALS mutant FUS proteins are recruited into stress granules in induced pluripotent stem cell-derived motoneurons
title_fullStr	ALS mutant FUS proteins are recruited into stress granules in induced pluripotent stem cell-derived motoneurons
title_full_unstemmed	ALS mutant FUS proteins are recruited into stress granules in induced pluripotent stem cell-derived motoneurons
title_sort	als mutant fus proteins are recruited into stress granules in induced pluripotent stem cell-derived motoneurons
description	Patient-derived induced pluripotent stem cells (iPSCs) provide an opportunity to study human diseases mainly in those cases for which no suitable model systems are available. Here, we have taken advantage of in vitro iPSCs derived from patients affected by amyotrophic lateral sclerosis (ALS) and carrying mutations in the RNA-binding protein FUS to study the cellular behavior of the mutant proteins in the appropriate genetic background. Moreover, the ability to differentiate iPSCs into spinal cord neural cells provides an in vitro model mimicking the physiological conditions. iPSCs were derived from FUSR514S and FUSR521C patient fibroblasts, whereas in the case of the severe FUSP525L mutation, in which fibroblasts were not available, a heterozygous and a homozygous iPSC line were raised by TALEN-directed mutagenesis. We show that aberrant localization and recruitment of FUS into stress granules (SGs) is a prerogative of the FUS mutant proteins and occurs only upon induction of stress in both undifferentiated iPSCs and spinal cord neural cells. Moreover, we show that the incorporation into SGs is proportional to the amount of cytoplasmic FUS, strongly correlating with the cytoplasmic delocalization phenotype of the different mutants. Therefore, the available iPSCs represent a very powerful system for understanding the correlation between FUS mutations, the molecular mechanisms of SG formation and ALS ethiopathogenesis.
publisher	The Company of Biologists
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486861/
_version_	1613242113049231360

ALS mutant FUS proteins are recruited into stress granules in induced pluripotent stem cell-derived motoneurons

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