Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS.

TDP-43 and FUS are RNA-binding proteins that form cytoplasmic inclusions in some forms of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Moreover, mutations in TDP-43 and FUS are linked to ALS and FTLD. However, it is unknown whether TDP-43 and FUS aggregate and ca...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Zhihui Sun, Zamia Diaz, Xiaodong Fang, Michael P Hart, Alessandra Chesi, James Shorter, Aaron D Gitler
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/64a3f308d78a49eab033d0f03286c4d2
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:64a3f308d78a49eab033d0f03286c4d2
record_format	dspace
spelling	oai:doaj.org-article:64a3f308d78a49eab033d0f03286c4d22021-11-18T05:36:13ZMolecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS.1544-91731545-788510.1371/journal.pbio.1000614https://doaj.org/article/64a3f308d78a49eab033d0f03286c4d22011-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21541367/pdf/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885TDP-43 and FUS are RNA-binding proteins that form cytoplasmic inclusions in some forms of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Moreover, mutations in TDP-43 and FUS are linked to ALS and FTLD. However, it is unknown whether TDP-43 and FUS aggregate and cause toxicity by similar mechanisms. Here, we exploit a yeast model and purified FUS to elucidate mechanisms of FUS aggregation and toxicity. Like TDP-43, FUS must aggregate in the cytoplasm and bind RNA to confer toxicity in yeast. These cytoplasmic FUS aggregates partition to stress granule compartments just as they do in ALS patients. Importantly, in isolation, FUS spontaneously forms pore-like oligomers and filamentous structures reminiscent of FUS inclusions in ALS patients. FUS aggregation and toxicity requires a prion-like domain, but unlike TDP-43, additional determinants within a RGG domain are critical for FUS aggregation and toxicity. In further distinction to TDP-43, ALS-linked FUS mutations do not promote aggregation. Finally, genome-wide screens uncovered stress granule assembly and RNA metabolism genes that modify FUS toxicity but not TDP-43 toxicity. Our findings suggest that TDP-43 and FUS, though similar RNA-binding proteins, aggregate and confer disease phenotypes via distinct mechanisms. These differences will likely have important therapeutic implications.Zhihui SunZamia DiazXiaodong FangMichael P HartAlessandra ChesiJames ShorterAaron D GitlerPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 9, Iss 4, p e1000614 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Zhihui Sun Zamia Diaz Xiaodong Fang Michael P Hart Alessandra Chesi James Shorter Aaron D Gitler Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS.
description	TDP-43 and FUS are RNA-binding proteins that form cytoplasmic inclusions in some forms of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Moreover, mutations in TDP-43 and FUS are linked to ALS and FTLD. However, it is unknown whether TDP-43 and FUS aggregate and cause toxicity by similar mechanisms. Here, we exploit a yeast model and purified FUS to elucidate mechanisms of FUS aggregation and toxicity. Like TDP-43, FUS must aggregate in the cytoplasm and bind RNA to confer toxicity in yeast. These cytoplasmic FUS aggregates partition to stress granule compartments just as they do in ALS patients. Importantly, in isolation, FUS spontaneously forms pore-like oligomers and filamentous structures reminiscent of FUS inclusions in ALS patients. FUS aggregation and toxicity requires a prion-like domain, but unlike TDP-43, additional determinants within a RGG domain are critical for FUS aggregation and toxicity. In further distinction to TDP-43, ALS-linked FUS mutations do not promote aggregation. Finally, genome-wide screens uncovered stress granule assembly and RNA metabolism genes that modify FUS toxicity but not TDP-43 toxicity. Our findings suggest that TDP-43 and FUS, though similar RNA-binding proteins, aggregate and confer disease phenotypes via distinct mechanisms. These differences will likely have important therapeutic implications.
format	article
author	Zhihui Sun Zamia Diaz Xiaodong Fang Michael P Hart Alessandra Chesi James Shorter Aaron D Gitler
author_facet	Zhihui Sun Zamia Diaz Xiaodong Fang Michael P Hart Alessandra Chesi James Shorter Aaron D Gitler
author_sort	Zhihui Sun
title	Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS.
title_short	Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS.
title_full	Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS.
title_fullStr	Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS.
title_full_unstemmed	Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS.
title_sort	molecular determinants and genetic modifiers of aggregation and toxicity for the als disease protein fus/tls.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/64a3f308d78a49eab033d0f03286c4d2
work_keys_str_mv	AT zhihuisun moleculardeterminantsandgeneticmodifiersofaggregationandtoxicityforthealsdiseaseproteinfustls AT zamiadiaz moleculardeterminantsandgeneticmodifiersofaggregationandtoxicityforthealsdiseaseproteinfustls AT xiaodongfang moleculardeterminantsandgeneticmodifiersofaggregationandtoxicityforthealsdiseaseproteinfustls AT michaelphart moleculardeterminantsandgeneticmodifiersofaggregationandtoxicityforthealsdiseaseproteinfustls AT alessandrachesi moleculardeterminantsandgeneticmodifiersofaggregationandtoxicityforthealsdiseaseproteinfustls AT jamesshorter moleculardeterminantsandgeneticmodifiersofaggregationandtoxicityforthealsdiseaseproteinfustls AT aarondgitler moleculardeterminantsandgeneticmodifiersofaggregationandtoxicityforthealsdiseaseproteinfustls
_version_	1718424915772702720

Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS.

Ejemplares similares