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

Leeanne McGurk, Edward Gomes, Lin Guo, Jelena Mojsilovic-Petrovic, Van Tran, Robert G. Kalb, James Shorter, Nancy M. Bonini (Lead / Corresponding author)

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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. McGurk et al. show that TDP-43 is a PAR-binding protein and that this function stimulates liquid-liquid phase separation and stress granule localization. Under short-term stress, the stress granule protects TDP-43 from phosphorylation. TDP-43 foci that persist during long-term stress transition into the phosphorylated state. Inhibition of the PARP Tankyrase mitigates both the cytoplasmic accumulation of TDP-43 and neuronal degeneration.

Original languageEnglish
Pages (from-to)703-717.e9
Number of pages24
JournalMolecular Cell
Volume71
Issue number5
Early online date9 Aug 2018
DOIs
Publication statusPublished - 6 Sep 2018

Keywords

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

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    McGurk, L., Gomes, E., Guo, L., Mojsilovic-Petrovic, J., Tran, V., Kalb, R. G., Shorter, J., & Bonini, N. M. (2018). Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization. Molecular Cell, 71(5), 703-717.e9. https://doi.org/10.1016/j.molcel.2018.07.002