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, CS; Ascher, DB; Reid, GE; Hatters, DM

Author(s): 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, CS; Ascher, DB; Reid, GE; Hatters, DM;
Details: Publication Year 2017-05-02,Volume 19,Issue #5,Page 919-927
Journal Title: Cell Reports
Publication Type: Journal Article
Abstract: 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.
Publisher: eLIFE
Research Division(s): Cell Signalling And Cell Death
PubMed ID: 28467905
Publisher's Version: https://doi.org/10.1016/j.celrep.2017.04.029
Open Access at Publisher's Site: http://www.sciencedirect.com/science/article/pii/S2211124717305235
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Ramdzan YM et al_Cell Reports 2017.pdf - (1.95MB, application/pdf)

Creation Date: 2017-05-15 01:16:30

Last Modified: 2017-05-15 03:00:07