Poly(ADP-ribose) Engages the TDP-43 Nuclear-Localization Sequence to Regulate Granulo-Filamentous Aggregation

Leeanne McGurk, Edward Gomes, Lin Guo, James Shorter (Lead / Corresponding author), Nancy M. Bonini (Lead / Corresponding author)

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

TAR DNA-binding protein of 43 kDa (TDP-43) forms granulo-filamentous aggregates in affected brain regions of >95% of patients with ALS and ∼50% of patients with frontotemporal degeneration (FTD). Furthermore, in disease, TDP-43 becomes N-terminally truncated resulting in protein deposits that are mainly composed of the C-terminal prion-like domain (PrLD). The PrLD is inherently aggregation-prone and is hypothesized to drive protein aggregation of TDP-43 in disease. Here, we establish that the N-terminal region of the protein is critical for rapid TDP-43 granulo-filamentous aggregation. We show that the biopolymer poly(ADP-ribose), or PAR, inhibits granulo-filamentous aggregation of TDP-43 by engaging PAR-binding motifs (PBMs) embedded in the TDP-43 nuclear-localization sequence. We demonstrate that progressive N-terminal truncation of TDP-43 can decelerate aggregation kinetics and promote formation of thread-like filaments. Thus, the N-terminal region and the PBMs of TDP-43 promote rapid granulo-filamentous aggregation and antagonize formation of thread-like fibrils. These findings illustrate the complexity of TDP-43 aggregation trajectories.

Original languageEnglish
Pages (from-to)6923-6926
Number of pages4
JournalBiochemistry
Volume57
Issue number51
Early online date12 Dec 2018
DOIs
Publication statusPublished - 26 Dec 2018

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