Huntingtin Inclusions Trigger Cellular Quiescence, Deactivate Apoptosis, and Lead to Delayed Necrosis

Yasmin M. Ramdzan, Mikhail M. Trubetskov, Angelique R Ormsby, Estella A. Newcombe, Xiaojing Sui, Mark J. Tobin, Marie N. Bongiovanni, Sally Louise Gras, Grant Dewson, Jason M.L. Miller, Steven Finkbeiner, Nagaraj S. Moily, Jonathan Niclis, Clare L. Parish, Anthony W. Purcell, Michael J Baker, Jacqueline A. Wilce, Saboora Waris, Diana Stojanovski, Till BöckingChing-Seng Ang, David B Ascher, Gavin E. Reid, Danny M. Hatters

Research output: Contribution to journalArticleResearchpeer-review

43 Citations (Scopus)

Abstract

Competing models exist in the literature for the relationship between mutant Huntingtin exon 1 (Httex1) inclusion formation and toxicity. In one, inclusions are adaptive by sequestering the proteotoxicity of soluble Httex1. In the other, inclusions compromise cellular activity as a result of proteome co-aggregation. Using a biosensor of Httex1 conformation in mammalian cell models, we discovered a mechanism that reconciles these competing models. Newly formed inclusions were composed of disordered Httex1 and ribonucleoproteins. As inclusions matured, Httex1 reconfigured into amyloid, and other glutamine-rich and prion domain-containing proteins were recruited. Soluble Httex1 caused a hyperpolarized mitochondrial membrane potential, increased reactive oxygen species, and promoted apoptosis. Inclusion formation triggered a collapsed mitochondrial potential, cellular quiescence, and deactivated apoptosis. We propose a revised model where sequestration of soluble Httex1 inclusions can remove the trigger for apoptosis but also co-aggregate other proteins, which curtails cellular metabolism and leads to a slow death by necrosis.

Original languageEnglish
Pages (from-to)919-927
Number of pages9
JournalCell Reports
Volume19
Issue number5
DOIs
Publication statusPublished - 2 May 2017

Keywords

  • flow cytometry
  • Huntington's disease
  • P bodies
  • ribosome quality control
  • RNA granule
  • stress granule
  • translation

Cite this

Ramdzan, Y. M., Trubetskov, M. M., Ormsby, A. R., Newcombe, E. A., Sui, X., Tobin, M. J., Bongiovanni, M. N., Gras, S. L., Dewson, G., Miller, J. M. L., Finkbeiner, S., Moily, N. S., Niclis, J., Parish, C. L., Purcell, A. W., Baker, M. J., Wilce, J. A., Waris, S., Stojanovski, D., ... Hatters, D. M. (2017). Huntingtin Inclusions Trigger Cellular Quiescence, Deactivate Apoptosis, and Lead to Delayed Necrosis. Cell Reports, 19(5), 919-927. https://doi.org/10.1016/j.celrep.2017.04.029