4-Phenylbutyrate ameliorates apoptotic neural cell death in Down syndrome by reducing protein aggregates

Abstract Individuals with Down syndrome (DS) commonly show unique pathological phenotypes throughout their life span. Besides the specific effects of dosage-sensitive genes on chromosome 21, recent studies have demonstrated that the gain of a chromosome exerts an adverse impact on cell physiology, r...

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Autores principales:	Katsuya Hirata, Toshihiko Nambara, Keiji Kawatani, Nobutoshi Nawa, Hidetaka Yoshimatsu, Haruna Kusakabe, Kimihiko Banno, Ken Nishimura, Manami Ohtaka, Mahito Nakanishi, Hidetoshi Taniguchi, Hitomi Arahori, Kazuko Wada, Keiichi Ozono, Yasuji Kitabatake
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3cbef660897d48f4be8bf945fdb9d169
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spelling	oai:doaj.org-article:3cbef660897d48f4be8bf945fdb9d1692021-12-02T16:45:45Z4-Phenylbutyrate ameliorates apoptotic neural cell death in Down syndrome by reducing protein aggregates10.1038/s41598-020-70362-x2045-2322https://doaj.org/article/3cbef660897d48f4be8bf945fdb9d1692020-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-70362-xhttps://doaj.org/toc/2045-2322Abstract Individuals with Down syndrome (DS) commonly show unique pathological phenotypes throughout their life span. Besides the specific effects of dosage-sensitive genes on chromosome 21, recent studies have demonstrated that the gain of a chromosome exerts an adverse impact on cell physiology, regardless of the karyotype. Although dysregulated transcription and perturbed protein homeostasis are observed in common in human fibroblasts with trisomy 21, 18, and 13, whether and how this aneuploidy-associated stress acts on other cell lineages and affects the pathophysiology are unknown. Here, we investigated cellular stress responses in human trisomy 21 and 13 neurons differentiated from patient-derived induced pluripotent stem cells. Neurons of both trisomies showed increased vulnerability to apoptotic cell death, accompanied by dysregulated protein homeostasis and upregulation of the endoplasmic reticulum stress pathway. In addition, misfolded protein aggregates, comprising various types of neurodegenerative disease-related proteins, were abnormally accumulated in trisomic neurons. Intriguingly, treatment with sodium 4-phenylbutyrate, a chemical chaperone, successfully decreased the formation of protein aggregates and prevented the progression of cell apoptosis in trisomic neurons. These results suggest that aneuploidy-associated stress might be a therapeutic target for the neurodegenerative phenotypes in DS.Katsuya HirataToshihiko NambaraKeiji KawataniNobutoshi NawaHidetaka YoshimatsuHaruna KusakabeKimihiko BannoKen NishimuraManami OhtakaMahito NakanishiHidetoshi TaniguchiHitomi ArahoriKazuko WadaKeiichi OzonoYasuji KitabatakeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-14 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Katsuya Hirata Toshihiko Nambara Keiji Kawatani Nobutoshi Nawa Hidetaka Yoshimatsu Haruna Kusakabe Kimihiko Banno Ken Nishimura Manami Ohtaka Mahito Nakanishi Hidetoshi Taniguchi Hitomi Arahori Kazuko Wada Keiichi Ozono Yasuji Kitabatake 4-Phenylbutyrate ameliorates apoptotic neural cell death in Down syndrome by reducing protein aggregates
description	Abstract Individuals with Down syndrome (DS) commonly show unique pathological phenotypes throughout their life span. Besides the specific effects of dosage-sensitive genes on chromosome 21, recent studies have demonstrated that the gain of a chromosome exerts an adverse impact on cell physiology, regardless of the karyotype. Although dysregulated transcription and perturbed protein homeostasis are observed in common in human fibroblasts with trisomy 21, 18, and 13, whether and how this aneuploidy-associated stress acts on other cell lineages and affects the pathophysiology are unknown. Here, we investigated cellular stress responses in human trisomy 21 and 13 neurons differentiated from patient-derived induced pluripotent stem cells. Neurons of both trisomies showed increased vulnerability to apoptotic cell death, accompanied by dysregulated protein homeostasis and upregulation of the endoplasmic reticulum stress pathway. In addition, misfolded protein aggregates, comprising various types of neurodegenerative disease-related proteins, were abnormally accumulated in trisomic neurons. Intriguingly, treatment with sodium 4-phenylbutyrate, a chemical chaperone, successfully decreased the formation of protein aggregates and prevented the progression of cell apoptosis in trisomic neurons. These results suggest that aneuploidy-associated stress might be a therapeutic target for the neurodegenerative phenotypes in DS.
format	article
author	Katsuya Hirata Toshihiko Nambara Keiji Kawatani Nobutoshi Nawa Hidetaka Yoshimatsu Haruna Kusakabe Kimihiko Banno Ken Nishimura Manami Ohtaka Mahito Nakanishi Hidetoshi Taniguchi Hitomi Arahori Kazuko Wada Keiichi Ozono Yasuji Kitabatake
author_facet	Katsuya Hirata Toshihiko Nambara Keiji Kawatani Nobutoshi Nawa Hidetaka Yoshimatsu Haruna Kusakabe Kimihiko Banno Ken Nishimura Manami Ohtaka Mahito Nakanishi Hidetoshi Taniguchi Hitomi Arahori Kazuko Wada Keiichi Ozono Yasuji Kitabatake
author_sort	Katsuya Hirata
title	4-Phenylbutyrate ameliorates apoptotic neural cell death in Down syndrome by reducing protein aggregates
title_short	4-Phenylbutyrate ameliorates apoptotic neural cell death in Down syndrome by reducing protein aggregates
title_full	4-Phenylbutyrate ameliorates apoptotic neural cell death in Down syndrome by reducing protein aggregates
title_fullStr	4-Phenylbutyrate ameliorates apoptotic neural cell death in Down syndrome by reducing protein aggregates
title_full_unstemmed	4-Phenylbutyrate ameliorates apoptotic neural cell death in Down syndrome by reducing protein aggregates
title_sort	4-phenylbutyrate ameliorates apoptotic neural cell death in down syndrome by reducing protein aggregates
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/3cbef660897d48f4be8bf945fdb9d169
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4-Phenylbutyrate ameliorates apoptotic neural cell death in Down syndrome by reducing protein aggregates

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