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

Publication date: 2 May 2017
Source:Cell Reports, Volume 19, Issue 5
Author(s): Yasmin M. Ramdzan, Mikhail M. Trubetskov, Angelique R. Ormsby, Estella A. Newcombe, Xiaojing Sui, Mark J. Tobin, Marie N. Bongiovanni, Sally L. 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 Böcking, Ching-Seng Ang, David B. Ascher, Gavin E. Reid, Danny M. Hatters
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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Teaser

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.


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