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Cell Rep. 2017 May 2;19(5):919-927. doi: 10.1016/j.celrep.2017.04.029.

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

Author information

1
Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
2
Australian Synchrotron, 800 Blackburn Road, Clayton, VIC 3168, Australia.
3
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
4
Department of Chemical and Biomolecular Engineering and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
5
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.
6
University of Michigan Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105, USA.
7
Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158-2261, USA.
8
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3010, Australia.
9
Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
10
School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
11
Bio21 Mass Spectrometry and Proteomics Facility, The University of Melbourne, Melbourne, VIC 3010, Australia.
12
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.
13
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.

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.

KEYWORDS:

Huntington’s disease; P bodies; RNA granule; flow cytometry; ribosome quality control; stress granule; translation

PMID:
28467905
DOI:
10.1016/j.celrep.2017.04.029
[Indexed for MEDLINE]
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