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

Autor:	Ramdzan YM; Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia., Trubetskov MM; Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia., Ormsby AR; Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia., Newcombe EA; Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia., Sui X; Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia., Tobin MJ; Australian Synchrotron, 800 Blackburn Road, Clayton, VIC 3168, Australia., Bongiovanni MN; Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK., Gras SL; Department of Chemical and Biomolecular Engineering and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia., Dewson G; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Melbourne, VIC 3010, Australia., Miller JML; University of Michigan Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105, USA., Finkbeiner S; Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158-2261, USA., Moily NS; Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia., Niclis J; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3010, Australia., Parish CL; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3010, Australia., Purcell AW; Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia., Baker MJ; Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia., Wilce JA; Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia., Waris S; Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia., Stojanovski D; Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia., Böcking T; School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia., Ang CS; Bio21 Mass Spectrometry and Proteomics Facility, The University of Melbourne, Melbourne, VIC 3010, Australia., Ascher DB; Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia., Reid GE; Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia; School of Chemistry, The University of Melbourne, Melbourne, VIC 3010, Australia., Hatters DM; Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia. Electronic address: dhatters@unimelb.edu.au.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2017 May 02; Vol. 19 (5), pp. 919-927.
DOI:	10.1016/j.celrep.2017.04.029
Abstrakt:	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. (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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