Elimination of protein aggregates prevents premature senescence in human trisomy 21 fibroblasts.

Nobutoshi Nawa,Kimihiko Banno,Keiichi Ozono,Yasuji Kitabatake,Hitomi Arahori,Daisuke Okuzaki,Sayaka Omori,Mahito Nakanishi,Toshihiko Nambara,Hidetoshi Taniguchi,Junji Takeda,Kazuko Wada,Keiji Kawatani,Manami Ohtaka,Chikara Kokubu,Katsuya Hirata,Ken Nishimura

doi:10.1371/journal.pone.0219592

Abstract

Chromosome abnormalities induces profound alterations in gene expression, leading to various disease phenotypes. Recent studies on yeast and mammalian cells have demonstrated that aneuploidy exerts detrimental effects on organismal growth and development, regardless of the karyotype, suggesting that aneuploidy-associated stress plays an important role in disease pathogenesis. However, whether and how this effect alters cellular homeostasis and long-term features of human disease are not fully understood. Here, we aimed to investigate cellular stress responses in human trisomy syndromes, using fibroblasts and induced pluripotent stem cells (iPSCs). Dermal fibroblasts derived from patients with trisomy 21, 18 and 13 showed a severe impairment of cell proliferation and enhanced premature senescence. These phenomena were accompanied by perturbation of protein homeostasis, leading to the accumulation of protein aggregates. We found that treatment with sodium 4-phenylbutyrate (4-PBA), a chemical chaperone, decreased the protein aggregates in trisomy fibroblasts. Notably, 4-PBA treatment successfully prevented the progression of premature senescence in secondary fibroblasts derived from trisomy 21 iPSCs. Our study reveals aneuploidy-associated stress as a potential therapeutic target for human trisomies, including Down syndrome.

Highlights

Down syndrome (DS; trisomy 21) is the most common chromosomal abnormality, affecting 1 in 650–1000 births [1]
transferase-mediated dUTP nick end labeling (TUNEL)-positive cells were significantly increased in trisomy 21, but the difference was relatively small, and no similar change was seen in trisomy 18 and 13 cells, suggesting that apoptotic cell death was not the primary cause of reduced proliferation in trisomy cells (Fig 1B)
These results suggest that chromosome aneuploidy induces common physiological phenotypes, which are associated with the numbers of the genes located on the affected chromosomes

Summary

Introduction

Down syndrome (DS; trisomy 21) is the most common chromosomal abnormality, affecting 1 in 650–1000 births [1]. Most cases of DS have an extra copy of chromosome 21, exhibiting various types of clinical complications including intellectual disability, congenital heart defects and hematopoietic abnormalities. These phenotypes are generally thought to be a direct result of cumulative effects caused by increased expression of a specific subset of genes located on chromosome 21. Intensive studies have been made to identify the combination of genes responsible for disease phenotypes, providing clues to decipher the molecular consequences of genome dosage imbalances. The clinical presentation of DS is complex and highly variable, and there seems not always to be a direct correlation between gene dosage and disease phenotypes, suggesting the existence of different mechanisms that can modify the gene-specific effect and have a strong impact on DS pathology

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