Seeding the aggregation of TDP-43 requires post-fibrillization proteolytic cleavage.
Nat Neurosci
; 26(6): 983-996, 2023 06.
Article
en En
| MEDLINE
| ID: mdl-37248338
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 ß-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.
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1
Base de datos:
MEDLINE
Asunto principal:
Degeneración Lobar Frontotemporal
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Demencia Frontotemporal
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Proteinopatías TDP-43
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Esclerosis Amiotrófica Lateral
Idioma:
En
Revista:
Nat Neurosci
Asunto de la revista:
NEUROLOGIA
Año:
2023
Tipo del documento:
Article