Version 2 2019-11-05, 18:13Version 2 2019-11-05, 18:13
Version 1 2018-12-14, 22:03Version 1 2018-12-14, 22:03
journal contribution
posted on 2019-11-05, 18:13authored byLeeanne McGurk, Edward Gomes, Lin Guo, James Shorter, Nancy M. Bonini
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.