Functional interaction between FUS and SMN underlies SMA-like splicing changes in wild-type hFUS mice

Abstract Several of the identified genetic factors in Amyotrophic Lateral Sclerosis (ALS) point to dysfunction in RNA processing as a major pathogenic mechanism. However, whether a precise RNA pathway is particularly affected remains unknown. Evidence suggests that FUS, that is mutated in familial A...

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Autores principales:	Alessia Mirra, Simona Rossi, Silvia Scaricamazza, Michela Di Salvio, Illari Salvatori, Cristiana Valle, Paola Rusmini, Angelo Poletti, Gianluca Cestra, Maria Teresa Carrì, Mauro Cozzolino
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/92047d0a186d4ca58aaaa2ebf2eb2856
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spelling	oai:doaj.org-article:92047d0a186d4ca58aaaa2ebf2eb28562021-12-02T12:31:48ZFunctional interaction between FUS and SMN underlies SMA-like splicing changes in wild-type hFUS mice10.1038/s41598-017-02195-02045-2322https://doaj.org/article/92047d0a186d4ca58aaaa2ebf2eb28562017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02195-0https://doaj.org/toc/2045-2322Abstract Several of the identified genetic factors in Amyotrophic Lateral Sclerosis (ALS) point to dysfunction in RNA processing as a major pathogenic mechanism. However, whether a precise RNA pathway is particularly affected remains unknown. Evidence suggests that FUS, that is mutated in familial ALS, and SMN, the causative factor in Spinal Muscular Atrophy (SMA), cooperate to the same molecular pathway, i.e. regulation of alternative splicing, and that disturbances in SMN-regulated functions, either caused by depletion of SMN protein (as in the case of SMA) or by pathogenic interactions between FUS and SMN (as in the case of ALS) might be a common theme in both diseases. In this work, we followed these leads and tested their pathogenic relevance in vivo. FUS-associated ALS recapitulates, in transgenic mice, crucial molecular features that characterise mouse models of SMA, including defects in snRNPs distribution and in the alternative splicing of genes important for motor neurons. Notably, altering SMN levels by haploinsufficiency or overexpression does not impact the phenotypes of mouse or Drosophila models of FUS-mediated toxicity. Overall, these findings suggest that FUS and SMN functionally interact and that FUS may act downstream of SMN-regulated snRNP assembly in the regulation of alternative splicing and gene expression.Alessia MirraSimona RossiSilvia ScaricamazzaMichela Di SalvioIllari SalvatoriCristiana VallePaola RusminiAngelo PolettiGianluca CestraMaria Teresa CarrìMauro CozzolinoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Alessia Mirra Simona Rossi Silvia Scaricamazza Michela Di Salvio Illari Salvatori Cristiana Valle Paola Rusmini Angelo Poletti Gianluca Cestra Maria Teresa Carrì Mauro Cozzolino Functional interaction between FUS and SMN underlies SMA-like splicing changes in wild-type hFUS mice
description	Abstract Several of the identified genetic factors in Amyotrophic Lateral Sclerosis (ALS) point to dysfunction in RNA processing as a major pathogenic mechanism. However, whether a precise RNA pathway is particularly affected remains unknown. Evidence suggests that FUS, that is mutated in familial ALS, and SMN, the causative factor in Spinal Muscular Atrophy (SMA), cooperate to the same molecular pathway, i.e. regulation of alternative splicing, and that disturbances in SMN-regulated functions, either caused by depletion of SMN protein (as in the case of SMA) or by pathogenic interactions between FUS and SMN (as in the case of ALS) might be a common theme in both diseases. In this work, we followed these leads and tested their pathogenic relevance in vivo. FUS-associated ALS recapitulates, in transgenic mice, crucial molecular features that characterise mouse models of SMA, including defects in snRNPs distribution and in the alternative splicing of genes important for motor neurons. Notably, altering SMN levels by haploinsufficiency or overexpression does not impact the phenotypes of mouse or Drosophila models of FUS-mediated toxicity. Overall, these findings suggest that FUS and SMN functionally interact and that FUS may act downstream of SMN-regulated snRNP assembly in the regulation of alternative splicing and gene expression.
format	article
author	Alessia Mirra Simona Rossi Silvia Scaricamazza Michela Di Salvio Illari Salvatori Cristiana Valle Paola Rusmini Angelo Poletti Gianluca Cestra Maria Teresa Carrì Mauro Cozzolino
author_facet	Alessia Mirra Simona Rossi Silvia Scaricamazza Michela Di Salvio Illari Salvatori Cristiana Valle Paola Rusmini Angelo Poletti Gianluca Cestra Maria Teresa Carrì Mauro Cozzolino
author_sort	Alessia Mirra
title	Functional interaction between FUS and SMN underlies SMA-like splicing changes in wild-type hFUS mice
title_short	Functional interaction between FUS and SMN underlies SMA-like splicing changes in wild-type hFUS mice
title_full	Functional interaction between FUS and SMN underlies SMA-like splicing changes in wild-type hFUS mice
title_fullStr	Functional interaction between FUS and SMN underlies SMA-like splicing changes in wild-type hFUS mice
title_full_unstemmed	Functional interaction between FUS and SMN underlies SMA-like splicing changes in wild-type hFUS mice
title_sort	functional interaction between fus and smn underlies sma-like splicing changes in wild-type hfus mice
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/92047d0a186d4ca58aaaa2ebf2eb2856
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Functional interaction between FUS and SMN underlies SMA-like splicing changes in wild-type hFUS mice

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