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Mol Cell. 2018 Sep 6;71(5):703-717.e9. doi: 10.1016/j.molcel.2018.07.002. Epub 2018 Aug 9.

Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization.

Author information

1
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Department of Neurology, Children's Hospital of Philadelphia, Joseph Stokes Jr. Research Institute, Philadelphia, PA 19104, USA.
4
Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jshorter@pennmedicine.upenn.edu.
5
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: nbonini@sas.upenn.edu.

Abstract

In amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD), cytoplasmic aggregates of hyperphosphorylated TDP-43 accumulate and colocalize with some stress granule components, but how pathological TDP-43 aggregation is nucleated remains unknown. In Drosophila, we establish that downregulation of tankyrase, a poly(ADP-ribose) (PAR) polymerase, reduces TDP-43 accumulation in the cytoplasm and potently mitigates neurodegeneration. We establish that TDP-43 non-covalently binds to PAR via PAR-binding motifs embedded within its nuclear localization sequence. PAR binding promotes liquid-liquid phase separation of TDP-43 in vitro and is required for TDP-43 accumulation in stress granules in mammalian cells and neurons. Stress granule localization initially protects TDP-43 from disease-associated phosphorylation, but upon long-term stress, stress granules resolve, leaving behind aggregates of phosphorylated TDP-43. Finally, small-molecule inhibition of Tankyrase-1/2 in mammalian cells inhibits formation of cytoplasmic TDP-43 foci without affecting stress granule assembly. Thus, Tankyrase inhibition antagonizes TDP-43-associated pathology and neurodegeneration and could have therapeutic utility for ALS and FTD.

KEYWORDS:

ALS; PARP; PARylation; TDP-43; Tankyrase; amyotrophic lateral sclerosis; motor neuron disease; phosphorylation; poly(ADP-ribose); stress granule

Comment in

PMID:
30100264
PMCID:
PMC6128762
[Available on 2019-09-06]
DOI:
10.1016/j.molcel.2018.07.002

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