Huntingtin N17-Domain Phosphorylation
Is a Well-Validated Therapeutic Target

  1. The oxidation or phosphorylation status of certain N17 residues determines huntingtin localization.
  2. The Serine 16 (S16) residue is hypophosphorylated on mutant huntingtin
  3. Restoring phosphorylation or using phosphomimetics on S16 in mutant huntingtin significantly mitigates toxicity
  4. Phosphoresistant S16>A16 models show increased toxicity
  5. CK2 neo-substrates can rescue S16 phosphorylation

Mitokinin compounds increase phospho-serine 16 in both in vitro and in vivo models. Publication forthcoming.


Di Pardo, A., V. Maglione, M. Alpaugh, M. Horkey, R. S. Atwal, J. Sassone, A. Ciammola, et al. "Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice." Proceedings of the National Academy of Sciences 109, no. 9 (2012), 3528-3533. doi:10.1073/pnas.1114502109.

Gu, Xiaofeng, Erin R. Greiner, Rakesh Mishra, Ravindra Kodali, Alex Osmand, Steven Finkbeiner, Joan S. Steffan, Leslie M. Thompson, Ronald Wetzel, and X. W. Yang. "Serines 13 and 16 Are Critical Determinants of Full-Length Human Mutant Huntingtin Induced Disease Pathogenesis in HD Mice." Neuron 64, no. 6 (2009), 828-840. doi:10.1016/j.neuron.2009.11.020.