Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis

L. McGurk, J. Mojsilovic-Petrovic, V. M. Van Deerlin, J. Shorter, R. G. Kalb, V. M. Lee, J. Q. Trojanowski, E. B. Lee, N. M. Bonini (Lead / Corresponding author)

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Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating and fatal motor neuron disease. Diagnosis typically occurs in the fifth decade of life and the disease progresses rapidly leading to death within ~ 2–5 years of symptomatic onset. There is no cure, and the few available treatments offer only a modest extension in patient survival. A protein central to ALS is the nuclear RNA/DNA-binding protein, TDP-43. In > 95% of ALS patients, TDP-43 is cleared from the nucleus and forms phosphorylated protein aggregates in the cytoplasm of affected neurons and glia. We recently defined that poly(ADP-ribose) (PAR) activity regulates TDP-43-associated toxicity. PAR is a posttranslational modification that is attached to target proteins by PAR polymerases (PARPs). PARP-1 and PARP-2 are the major enzymes that are active in the nucleus. Here, we uncovered that the motor neurons of the ALS spinal cord were associated with elevated nuclear PAR, suggesting elevated PARP activity. Veliparib, a small-molecule inhibitor of nuclear PARP-1/2, mitigated the formation of cytoplasmic TDP-43 aggregates in mammalian cells. In primary spinal-cord cultures from rat, Veliparib also inhibited TDP-43-associated neuronal death. These studies uncover that PAR activity is misregulated in the ALS spinal cord, and a small-molecular inhibitor of PARP-1/2 activity may have therapeutic potential in the treatment of ALS and related disorders associated with abnormal TDP-43 homeostasis.

Original languageEnglish
Article number84
Pages (from-to)1-15
Number of pages15
JournalActa Neuropathologica Communications
Volume6
Issue number1
DOIs
Publication statusPublished - 29 Aug 2018

Keywords

  • ABT-888/Veliparib
  • Motor neuron disease
  • PAR
  • Parp
  • PARylation
  • Poly(ADP-ribose)
  • Primary neuron
  • TDP-43

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    McGurk, L., Mojsilovic-Petrovic, J., Van Deerlin, V. M., Shorter, J., Kalb, R. G., Lee, V. M., Trojanowski, J. Q., Lee, E. B., & Bonini, N. M. (2018). Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis. Acta Neuropathologica Communications, 6(1), 1-15. [84]. https://doi.org/10.1186/s40478-018-0586-1