期刊
BIOCHEMISTRY
卷 57, 期 51, 页码 6923-6926出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.8b00910
关键词
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资金
- Ellison Medical Foundation
- American Federation for Aging Research
- Alzheimer's Association
- Life Extension Foundation
- ALS Association
- Department of Biochemistry and Biophysics Pilot Grant
- Packard Center for ALS Research at Johns Hopkins
- NIH [R0IGM099836, R21NS090205, SR01NS073660, R35NS097275]
- Target ALS
- Glenn Foundation
TAR DNA-binding protein of 43 kDa (TDP-43) forms granulo-filamentous aggregates in affected brain regions of >95% of patients with ALS and similar to 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.
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