Seeding the aggregation of TDP-43 requires post-fibrillization proteolytic cleavage

作者：Senthil T. Kumar, Sergey Nazarov, Sílvia Porta, Niran Maharjan, Urszula Cendrowska, Malek Kabani, Francesco Finamore, Yan Xu, Virginia M.‐Y. Lee, Hilal A. Lashuel · 发表于：Nature Neuroscience · 年份：2023 · DOI：10.1038/s41593-023-01341-4 · 被引用次数：91 · 研究领域：Amyotrophic Lateral Sclerosis Research、Parkinson's Disease Mechanisms and Treatments、Prion Diseases and Protein Misfolding

Despite the strong evidence linking the transactive response DNA-binding protein 43 (TDP-43) aggregation to the pathogenesis of frontotemporal lobar degeneration with TDP-43, amyotrophic lateral sclerosis and several neurodegenerative diseases, our knowledge of the sequence and structural determinants of its aggregation and neurotoxicity remains incomplete. Herein, we present a new method for producing recombinant full-length TDP-43 filaments that exhibit sequence and morphological features similar to those of brain-derived TDP-43 filaments. We show that TDP-43 filaments contain a β-sheet-rich helical amyloid core that is fully buried by the flanking structured domains of the protein. We demonstrate that the proteolytic cleavage of TDP-43 filaments and exposure of this amyloid core are necessary for propagating TDP-43 pathology and enhancing the seeding of brain-derived TDP-43 aggregates. Only TDP-43 filaments with exposed amyloid core efficiently seeded the aggregation of endogenous TDP-43 in cells. These findings suggest that inhibiting the enzymes mediating cleavage of TDP-43 aggregates represents a viable disease-modifying strategy to slow the progression of amyotrophic lateral sclerosis and other TDP-43 proteinopathies.