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Biochemistry. 2018 Dec 12. doi: 10.1021/acs.biochem.8b00910. [Epub ahead of print]

Poly(ADP-ribose) engages the TDP-43 nuclear-localization sequence to regulate granulo-filamentous aggregation.

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 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.

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