論文

査読有り 国際誌
2020年8月20日

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

Scientific reports
  • 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

10
1
開始ページ
14047
終了ページ
14047
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/s41598-020-70362-x

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.

リンク情報
DOI
https://doi.org/10.1038/s41598-020-70362-x
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32820178
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441064

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