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

YM Ramdzan; MM Trubetskov; AR Ormsby; EA Newcombe; X Sui; MJ Tobin; MN Bongiovanni; SL Gras; G Dewson; JML Miller; S Finkbeiner; NS Moily; J Niclis; CL Parish; AW Purcell; MJ Baker; JA Wilce; S Waris; D Stojanovski; T Böcking; CS Ang; DB Ascher; GE Reid; DM Hatters

Journal article

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

YM Ramdzan, MM Trubetskov, AR Ormsby, EA Newcombe, X Sui, MJ Tobin, MN Bongiovanni, SL Gras, G Dewson, JML Miller, S Finkbeiner, NS Moily, J Niclis, CL Parish, AW Purcell, MJ Baker, JA Wilce, S Waris, D Stojanovski, T Böcking Show all

Cell Reports | CELL PRESS | Published : 2017

DOI: 10.1016/j.celrep.2017.04.029

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 hyperpo..

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University of Melbourne Researchers

Sally Gras Author

Grant Dewson Author

Clare Parish Author

Diana Stojanovski Author

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Grants

Awarded by Hereditary Disease Foundation

Funding Acknowledgements

This work was funded by a grant to D.M.H. from the Australian Research Council (FT120100039); grants/fellowships from the National Health and Medical Research Council Project to D.M.H. (APP1049458, APP1049459, and APP1102059), J.A.W. (APP1105801), A.W.P. (1044215), and D.B.A. (APP1072476); and a grant to D.M.H. from the Hereditary Disease Foundation. Part of this research was undertaken on the Infrared beamline at the Australian Synchrotron. This research was supported by the Victorian Life Sciences Computation Initiative, an initiative of the Victorian Government, Australia, at its Facility hosted at the University of Melbourne (UOM0017).