Amyotrophic Lateral Sclerosis associated FUS mutation shortens mitochondria and induces neurotoxicity

Abstract Amyotrophic Lateral Sclerosis (ALS) is a lethal neurodegenerative disorder that primarily affects motor neurons. Dominant mutations in the RNA binding protein Fused in Sarcoma (FUS) have been identified as causative factors of ALS. Mutation, R495X, results in a premature stop codon and indu...

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Autores principales:	Tadashi Nakaya, Manolis Maragkakis
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Mitochondria Shortening RX821002 Binding Aggressive Disease Phenotype Targetome Mitochondria Size Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cb8569e4b09147fbb1c3b6d12bdc69e5
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spelling	oai:doaj.org-article:cb8569e4b09147fbb1c3b6d12bdc69e52021-12-02T15:08:53ZAmyotrophic Lateral Sclerosis associated FUS mutation shortens mitochondria and induces neurotoxicity10.1038/s41598-018-33964-02045-2322https://doaj.org/article/cb8569e4b09147fbb1c3b6d12bdc69e52018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-33964-0https://doaj.org/toc/2045-2322Abstract Amyotrophic Lateral Sclerosis (ALS) is a lethal neurodegenerative disorder that primarily affects motor neurons. Dominant mutations in the RNA binding protein Fused in Sarcoma (FUS) have been identified as causative factors of ALS. Mutation, R495X, results in a premature stop codon and induces an aggressive disease phenotype by a largely unknown process. Here, we employ CLIP-Seq, RNA-Seq and Ribo-Seq in cultured neurons expressing R495X or wild-type FUS to identify the mutation effects on the FUS targetome and on the neuronal transcriptome at the expression and translation level, simultaneously. We report that, unlike wild-type FUS that binds on precursor mRNAs (pre-mRNAs), R495X binds mature mRNAs in the cytoplasm. R495X has a moderate effect on target mRNA expression and its binding induces only modest expression changes. In contrast, we find that R495X controls the translation of genes that are associated with mitochondria function and results in significant reduction of mitochondrial size. Importantly, we show that introduction of the 4FL mutation that alters binding of R495X to RNA, partially abrogates R495X-induced effects on mRNA translation, mitochondrial size and neurotoxicity. Our findings uncover a novel RNA-mediated pathway of FUS R495X-induced neurotoxicity that affects mitochondria morphology and provide insight to previous studies associating mitochondria dysfunction to ALS.Tadashi NakayaManolis MaragkakisNature PortfolioarticleMitochondria ShorteningRX821002 BindingAggressive Disease PhenotypeTargetomeMitochondria SizeMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-15 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mitochondria Shortening RX821002 Binding Aggressive Disease Phenotype Targetome Mitochondria Size Medicine R Science Q
spellingShingle	Mitochondria Shortening RX821002 Binding Aggressive Disease Phenotype Targetome Mitochondria Size Medicine R Science Q Tadashi Nakaya Manolis Maragkakis Amyotrophic Lateral Sclerosis associated FUS mutation shortens mitochondria and induces neurotoxicity
description	Abstract Amyotrophic Lateral Sclerosis (ALS) is a lethal neurodegenerative disorder that primarily affects motor neurons. Dominant mutations in the RNA binding protein Fused in Sarcoma (FUS) have been identified as causative factors of ALS. Mutation, R495X, results in a premature stop codon and induces an aggressive disease phenotype by a largely unknown process. Here, we employ CLIP-Seq, RNA-Seq and Ribo-Seq in cultured neurons expressing R495X or wild-type FUS to identify the mutation effects on the FUS targetome and on the neuronal transcriptome at the expression and translation level, simultaneously. We report that, unlike wild-type FUS that binds on precursor mRNAs (pre-mRNAs), R495X binds mature mRNAs in the cytoplasm. R495X has a moderate effect on target mRNA expression and its binding induces only modest expression changes. In contrast, we find that R495X controls the translation of genes that are associated with mitochondria function and results in significant reduction of mitochondrial size. Importantly, we show that introduction of the 4FL mutation that alters binding of R495X to RNA, partially abrogates R495X-induced effects on mRNA translation, mitochondrial size and neurotoxicity. Our findings uncover a novel RNA-mediated pathway of FUS R495X-induced neurotoxicity that affects mitochondria morphology and provide insight to previous studies associating mitochondria dysfunction to ALS.
format	article
author	Tadashi Nakaya Manolis Maragkakis
author_facet	Tadashi Nakaya Manolis Maragkakis
author_sort	Tadashi Nakaya
title	Amyotrophic Lateral Sclerosis associated FUS mutation shortens mitochondria and induces neurotoxicity
title_short	Amyotrophic Lateral Sclerosis associated FUS mutation shortens mitochondria and induces neurotoxicity
title_full	Amyotrophic Lateral Sclerosis associated FUS mutation shortens mitochondria and induces neurotoxicity
title_fullStr	Amyotrophic Lateral Sclerosis associated FUS mutation shortens mitochondria and induces neurotoxicity
title_full_unstemmed	Amyotrophic Lateral Sclerosis associated FUS mutation shortens mitochondria and induces neurotoxicity
title_sort	amyotrophic lateral sclerosis associated fus mutation shortens mitochondria and induces neurotoxicity
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/cb8569e4b09147fbb1c3b6d12bdc69e5
work_keys_str_mv	AT tadashinakaya amyotrophiclateralsclerosisassociatedfusmutationshortensmitochondriaandinducesneurotoxicity AT manolismaragkakis amyotrophiclateralsclerosisassociatedfusmutationshortensmitochondriaandinducesneurotoxicity
_version_	1718388027790721024

Amyotrophic Lateral Sclerosis associated FUS mutation shortens mitochondria and induces neurotoxicity

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