Biochemistry and Pharmacology - Research Publications

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Author: Ascher, David × Author: Hatters, Daniel × Author: Haynes, Angelique × Author: Reid, Gavin × End date: 2019 × Start date: 2010 ×

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    Huntingtin Inclusions Trigger Cellular Quiescence, Deactivate Apoptosis, and Lead to Delayed Necrosis
    Ramdzan, YM ; Trubetskov, MM ; Ormsby, AR ; Newcombe, EA ; Sui, X ; Tobin, MJ ; Bongiovanni, MN ; Gras, SL ; Dewson, G ; Miller, JML ; Finkbeiner, S ; Moily, NS ; Niclis, J ; Parish, CL ; Purcell, AW ; Baker, MJ ; Wilce, JA ; Waris, S ; Stojanovski, D ; Bocking, T ; Ang, C-S ; Ascher, DB ; Reid, GE ; Hatters, DM (CELL PRESS, 2017-05-02)
    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.