Analysis of neuropathological phenotypes in Down syndrome based on the new disease concept

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15709
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Osaka University
• Principal Investigator: Nambara Toshihiko 大阪大学, 医学部附属病院, 医員 (00812166)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: iPS細胞 / ゲノム編集 / ダウン症候群

Outline of Final Research Achievements

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. 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. In addition, misfolded protein aggregates 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.

Free Research Field

小児科学

Academic Significance and Societal Importance of the Research Achievements

本研究において見出された‘Aneuploidy-associated stress’は、ダウン症神経細胞においてもアポトーシスという強い影響を与えていることが分かった。しかも4-PBAという化合物がその予防に奏効することを明らかにしたことで、今後ダウン症神経病態の治療薬となる可能性があるだろう。このことは平均寿命が60歳以上と長くなりつつあるダウン症者のQOL向上に役立つと期待できる。