Journal
CELL REPORTS
Volume 19, Issue 5, Pages 919-927Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.04.029
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Funding
- Australian Research Council [FT120100039]
- National Health and Medical Research Council [APP1049458, APP1049459, APP1102059, APP1105801, 1044215, APP1072476]
- Hereditary Disease Foundation
- Victorian Life Sciences Computation Initiative, an initiative of the Victorian Government, Australia [UOM0017]
- Australian Research Council [FT120100039] Funding Source: Australian Research Council
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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.
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