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

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. [Display omitted] •Soluble mutant Huntingtin exon 1 (Httex1) triggers apoptosis•Httex1 inclusions deactivate apoptosis but activate delayed necrosis•Nascent inclusions form from disordered Httex1 and ribosomes•Upon maturation, Httex1 converts into amyloid and co-recruits prion domain proteins Httex1 aggregation into inclusions has paradoxically been reported as either toxic or beneficial in Huntington’s disease. Ramdzan et al. define a dual mechanism of toxicity that explains this paradox. Soluble Httex1 triggers a fast death by apoptosis, whereas Httex1 inclusions invoke quiescence and redirect death to a slower necrotic pathway.