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

Cell Rep. 2017 May 2;19(5):919-927. doi: 10.1016/j.celrep.2017.04.029.


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.

Keywords: Huntington’s disease; P bodies; RNA granule; flow cytometry; ribosome quality control; stress granule; translation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / metabolism*
  • Apoptosis*
  • Exons
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Huntingtin Protein / genetics*
  • Huntingtin Protein / metabolism
  • Inclusion Bodies / metabolism
  • Membrane Potential, Mitochondrial
  • Mutation
  • Reactive Oxygen Species / metabolism
  • Ribonucleoproteins / genetics
  • Ribonucleoproteins / metabolism


  • Amyloid
  • HTT protein, human
  • Huntingtin Protein
  • Reactive Oxygen Species
  • Ribonucleoproteins