TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP.
TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP.
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DOI：
10.1038/s41586-023-06405-w
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发表时间：
2023-08
期刊：
影响因子：
64.8
通讯作者：
Ryskeldi-Falcon, Benjamin
中科院分区：
文献类型：
--
作者：
Arseni, Diana;Chen, Renren;Murzin, Alexey G.;Peak-Chew, Sew Y.;Garringer, Holly J.;Newell, Kathy L.;Kametani, Fuyuki;Robinson, Andrew C.;Vidal, Ruben;Ghetti, Bernardino;Hasegawa, Masato;Ryskeldi-Falcon, Benjamin
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). 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 FTLD. 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 dementia. We previously showed, using cryo-electron microscopy, that TDP-43 assembles into amyloid filaments in ALS and type B FTLD-TDP. 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. Cryo-electron microscopy structures and mass spectrometry analyses show that TAR DNA-binding protein 43 (TDP-43) forms amyloid filaments with a distinct fold in type A frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) compared with TDP-43 filaments in type B FTLD-TDP and amyotrophic lateral sclerosis.
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影响因子：
64.8
作者：
Cruts, Marc;Gijselinck, Ilse;Van Broeckhoven, Christine
通讯作者：
Van Broeckhoven, Christine
FTLD-TDP 组装体通过类似朊病毒的级联产生具有亚型特异性特征的新聚集体。
影响因子：
7.7
作者：
De Rossi P;Lewis AJ;Furrer J;De Vos L;Demeter T;Zbinden A;Zhong W;Wiersma VI;Scialo C;Weber J;Guo Z;Scaramuzza S;Di Fabrizio M;Böing C;Castaño-Díez D;Al-Amoudi A;Pérez-Berlanga M;Lashley T;Stahlberg H;Polymenidou M
通讯作者：
Polymenidou M
影响因子：
16.8
作者：
Cao, Qin;Boyer, David R.;Eisenberg, David S.
通讯作者：
Eisenberg, David S.
影响因子：
4
作者：
Ayala, Youhna M.;Zago, Paola;Baralle, Francisco E.
通讯作者：
Baralle, Francisco E.
影响因子：
64.8
作者：
Arseni D;Hasegawa M;Murzin AG;Kametani F;Arai M;Yoshida M;Ryskeldi-Falcon B
通讯作者：
Ryskeldi-Falcon B