Seeding the aggregation of TDP-43 requires post-fibrillization proteolytic cleavage. Academic Article uri icon

Overview

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 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.

publication date

  • May 29, 2023

Research

keywords

  • Amyotrophic Lateral Sclerosis
  • Frontotemporal Dementia
  • Frontotemporal Lobar Degeneration
  • TDP-43 Proteinopathies

Identity

PubMed Central ID

  • PMC10244175

Scopus Document Identifier

  • 85160401331

Digital Object Identifier (DOI)

  • 10.1038/s41593-023-01341-4

PubMed ID

  • 37248338

Additional Document Info

volume

  • 26

issue

  • 6