論文

査読有り 国際誌
2019年

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

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

14
7
開始ページ
e0219592
終了ページ
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1371/journal.pone.0219592

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.

リンク情報
DOI
https://doi.org/10.1371/journal.pone.0219592
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/31356639
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663065

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