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| Title | Seeding the aggregation of TDP-43 requires post-fibrillization proteolytic cleavage. |
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| Journal, issue, pages | Nat Neurosci, Vol. 26, Issue 6, Page 983-996, Year 2023 |
| Publish date | May 29, 2023 |
 Authors | Senthil T Kumar / Sergey Nazarov / Sílvia Porta / Niran Maharjan / Urszula Cendrowska / Malek Kabani / Francesco Finamore / Yan Xu / Virginia M-Y Lee / Hilal A Lashuel /   |
| PubMed Abstract | 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 ...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. |
 External links | Nat Neurosci / PubMed:37248338 / PubMed Central |
| Methods | EM (helical sym.) |
| Resolution | 3.7 Å |
| Structure data | EMDB-13795, PDB-7q3u: |
| Source |
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 Keywords |  RNA BINDING PROTEIN / TDP-43 / Amyloid / Neurodegeneration / Helical / Cryo-EM |
