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論文
- タイトル
- タイトル（英）
- Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology.
- 参照URL
- https://researchmap.jp/YuichiroMiyaoka/published_papers/41708605
- 著者
- 著者（英）
- Martina de Majo,Mark Koontz,Elise Marsan,Nir Salinas,Arren Ramsey,Yien-Ming Kuo,Kyounghee Seo,Huinan Li,Nina Dräger,Kun Leng,Santiago L Gonzales,Michael Kurnellas,Yuichiro Miyaoka,Joseph R Klim,Martin Kampmann,Michael E Ward,Eric J Huang,Erik M Ullian
- 担当区分
- 概要
- 概要（英）
- Loss of function (LoF) of TAR-DNA binding protein 43 (TDP-43) and mis-localization, together with TDP-43-positive and hyperphosphorylated inclusions, are found in post-mortem tissue of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those carrying LoF variants in the progranulin gene (GRN). Modeling TDP-43 pathology has been challenging in vivo and in vitro. We present a three-dimensional induced pluripotent stem cell (iPSC)-derived paradigm-mature brain organoids (mbOrg)-composed of cortical-like-astrocytes (iA) and neurons. When devoid of GRN, mbOrgs spontaneously recapitulate TDP-43 mis-localization, hyperphosphorylation, and LoF phenotypes. Mixing and matching genotypes in mbOrgs showed that GRN-/- iA are drivers for TDP-43 pathology. Finally, we rescued TDP-43 LoF by adding exogenous progranulin, demonstrating a link between TDP-43 LoF and progranulin expression. In conclusion, we present an iPSC-derived platform that shows striking features of human TDP-43 proteinopathy and provides a tool for the mechanistic modeling of TDP-43 pathology and patient-tailored therapeutic screening for FTD and ALS.
- 出版者・発行元
- 出版者・発行元（英）
- 誌名
- 誌名（英）
- Stem cell reports
- 巻
- 号
- 開始ページ
- 終了ページ
- 出版年月
- 2023年2月14日
- 査読の有無
- 招待の有無
- 掲載種別
- 研究論文（学術雑誌）
- ISSN
- DOI URL
- https://doi.org/10.1016/j.stemcr.2023.01.012
- 共同研究・競争的資金等の研究課題
研究者
宮岡 佑一郎
(ミヤオカ ユウイチロウ)