TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP

作者：Diana Arseni, Renren Chen, Alexey G. Murzin, Sew‐Yeu Peak‐Chew, Holly J. Garringer, Kathy L. Newell, Fuyuki Kametani, Andrew Robinson, Rubén Vidal, Bernardino Francesco Ghetti, Masato Hasegawa, Benjamin Falcon · 发表于：Nature · 年份：2023 · DOI：10.1038/s41586-023-06405-w · 被引用次数：175 · 研究领域：Amyotrophic Lateral Sclerosis Research、Prion Diseases and Protein Misfolding、Neurogenetic and Muscular Disorders Research

Abstract 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 FTLD 3–7 . 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 dementia 8 . We previously showed, using cryo-electron microscopy, that TDP-43 assembles into amyloid filaments in ALS and type B FTLD-TDP 9 . 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-trans...