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論文
- タイトル
- タイトル（英）
- TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP.
- 参照URL
- https://researchmap.jp/masatohasegawa/published_papers/43242533
- 著者
- 著者（英）
- Diana Arseni,Renren Chen,Alexey G Murzin,Sew Y Peak-Chew,Holly J Garringer,Kathy L Newell,Fuyuki Kametani,Andrew C Robinson,Ruben Vidal,Bernardino Ghetti,Masato Hasegawa,Benjamin Ryskeldi-Falcon
- 担当区分
- 概要
- 概要（英）
- The abnormal assembly of TAR DNA-binding protein 43 (TDP-43) in neuronal and glial cells characterizes nearly all cases of amyotrophic lateral sclerosis (ALS) and around half of cases of frontotemporal lobar degeneration (FTLD)1,2. A causal role for TDP-43 assembly in neurodegeneration is evidenced by dominantly inherited missense mutations in TARDBP, the gene encoding TDP-43, that promote assembly and give rise to ALS and FTLD3-7. At least four types (A-D) of FTLD with TDP-43 pathology (FTLD-TDP) are defined by distinct brain distributions of assembled TDP-43 and are associated with different clinical presentations of frontotemporal dementia8. We previously showed, using cryo-electron microscopy, that TDP-43 assembles into amyloid filaments in ALS and type B FTLD-TDP9. However, the structures of assembled TDP-43 in FTLD without ALS remained unknown. Here we report the cryo-electron microscopy structures of assembled TDP-43 from the brains of three individuals with the most common type of FTLD-TDP, type A. TDP-43 formed amyloid filaments with a new fold that was the same across individuals, indicating that this fold may characterize type A FTLD-TDP. The fold resembles a chevron badge and is unlike the double-spiral-shaped fold of ALS and type B FTLD-TDP, establishing that distinct filament folds of TDP-43 characterize different neurodegenerative conditions. The structures, in combination with mass spectrometry, led to the identification of two new post-translational modifications of assembled TDP-43, citrullination and monomethylation of R293, and indicate that they may facilitate filament formation and observed structural variation in individual filaments. The structures of TDP-43 filaments from type A FTLD-TDP will guide mechanistic studies of TDP-43 assembly, as well as the development of diagnostic and therapeutic compounds for TDP-43 proteinopathies.
- 出版者・発行元
- 出版者・発行元（英）
- 誌名
- 誌名（英）
- Nature
- 巻
- 620
- 号
- 7975
- 開始ページ
- 898
- 終了ページ
- 903
- 出版年月
- 2023年8月
- 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/10.1038/s41586-023-06405-w
- 共同研究・競争的資金等の研究課題
研究者
Hasegawa Masato
( )
,
亀谷 富由樹
(カメタニ フユキ)