Patient-derived induced Pluripotent Stem Cells (iPSCs) provide an opportunity to study human diseases mainly in those cases where no suitable model systems are available. Here we have taken advantage of in vitro iPSCs derived from patients affected by Amyotrophic Lateral Sclerosis and carrying mutations in the RNA-binding proteins 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 FUS(R514S) and FUS(R521C) patients' fibroblasts, while in the case of the severe FUS(P525L) mutation, where fibroblasts were not available, a heterozygous and a homozygous iPSC lines 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, nicely 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.

ALS mutant FUS proteins are recruited into stress granules in induced pluripotent stem cells- derived motoneurons / Lenzi, Jessica; DE SANTIS, Riccardo; Turris, Valeria de; Morlando, Mariangela; Laneve, Pietro; Calvo, Andrea; Caliendo, Virginia; Chiò, Adriano; Rosa, Alessandro; Bozzoni, Irene. - In: DISEASE MODELS & MECHANISMS. - ISSN 1754-8403. - ELETTRONICO. - 8:7(2015), pp. 755-766. [10.1242/dmm.020099]

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

LENZI, JESSICA;DE SANTIS, RICCARDO;MORLANDO, MARIANGELA;LANEVE, Pietro;ROSA, ALESSANDRO;BOZZONI, Irene
2015

Abstract

Patient-derived induced Pluripotent Stem Cells (iPSCs) provide an opportunity to study human diseases mainly in those cases where no suitable model systems are available. Here we have taken advantage of in vitro iPSCs derived from patients affected by Amyotrophic Lateral Sclerosis and carrying mutations in the RNA-binding proteins 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 FUS(R514S) and FUS(R521C) patients' fibroblasts, while in the case of the severe FUS(P525L) mutation, where fibroblasts were not available, a heterozygous and a homozygous iPSC lines 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, nicely 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.
2015
ALS; FUS; TALE nucleases; iPSCs
01 Pubblicazione su rivista::01a Articolo in rivista
ALS mutant FUS proteins are recruited into stress granules in induced pluripotent stem cells- derived motoneurons / Lenzi, Jessica; DE SANTIS, Riccardo; Turris, Valeria de; Morlando, Mariangela; Laneve, Pietro; Calvo, Andrea; Caliendo, Virginia; Chiò, Adriano; Rosa, Alessandro; Bozzoni, Irene. - In: DISEASE MODELS & MECHANISMS. - ISSN 1754-8403. - ELETTRONICO. - 8:7(2015), pp. 755-766. [10.1242/dmm.020099]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/805324
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