Journal article

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

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 ML 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 Bocking Show all

CELL REPORTS | CELL PRESS | Published : 2017

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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Grants

Awarded by Australian Research Council


Awarded by National Health and Medical Research Council


Awarded by Victorian Life Sciences Computation Initiative, an initiative of the Victorian Government, Australia


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).