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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doaj-3cbef660897d48f4be8bf945fdb9d1692021-08-22T11:20:04ZengNature Publishing GroupScientific Reports2045-23222020-08-0110111410.1038/s41598-020-70362-x4-Phenylbutyrate ameliorates apoptotic neural cell death in Down syndrome by reducing protein aggregatesKatsuya Hirata0Toshihiko Nambara1Keiji Kawatani2Nobutoshi Nawa3Hidetaka Yoshimatsu4Haruna Kusakabe5Kimihiko Banno6Ken Nishimura7Manami Ohtaka8Mahito Nakanishi9Hidetoshi Taniguchi10Hitomi Arahori11Kazuko Wada12Keiichi Ozono13Yasuji Kitabatake14Department of Pediatrics, Graduate School of Medicine, Osaka UniversityDepartment of Pediatrics, Graduate School of Medicine, Osaka UniversityDepartment of Pediatrics, Graduate School of Medicine, Osaka UniversityDepartment of Pediatrics, Graduate School of Medicine, Osaka UniversityDepartment of Pediatrics, Graduate School of Medicine, Osaka UniversityDepartment of Pediatrics, Graduate School of Medicine, Osaka UniversityDepartment of Pediatrics, Graduate School of Medicine, Osaka UniversityLaboratory of Gene Regulation, Faculty of Medicine, University of TsukubaBiotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST)Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST)Department of Pediatrics, Graduate School of Medicine, Osaka UniversityDepartment of Pediatrics, Graduate School of Medicine, Osaka UniversityDepartment of Pediatrics, Graduate School of Medicine, Osaka UniversityDepartment of Pediatrics, Graduate School of Medicine, Osaka UniversityDepartment of Pediatrics, Graduate School of Medicine, Osaka UniversityAbstract 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.https://doi.org/10.1038/s41598-020-70362-x |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
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 |
spellingShingle |
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 Scientific Reports |
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 Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2020-08-01 |
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. |
url |
https://doi.org/10.1038/s41598-020-70362-x |
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