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 Louise Gras, Grant Dewson, Jason M.L. 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 Böcking & 4 others Ching-Seng Ang, David B Ascher, Gavin E. Reid, Danny M. Hatters

Research output: Contribution to journalArticleResearchpeer-review

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)919-927
Number of pages9
JournalCell Reports
Volume19
Issue number5
DOIs
Publication statusPublished - 2 May 2017

Keywords

  • flow cytometry
  • Huntington's disease
  • P bodies
  • ribosome quality control
  • RNA granule
  • stress granule
  • translation

Cite this

Ramdzan, Y. M., Trubetskov, M. M., Ormsby, A. R., Newcombe, E. A., Sui, X., Tobin, M. J., ... Hatters, D. M. (2017). Huntingtin Inclusions Trigger Cellular Quiescence, Deactivate Apoptosis, and Lead to Delayed Necrosis. Cell Reports, 19(5), 919-927. https://doi.org/10.1016/j.celrep.2017.04.029
Ramdzan, Yasmin M. ; Trubetskov, Mikhail M. ; Ormsby, Angelique R ; Newcombe, Estella A. ; Sui, Xiaojing ; Tobin, Mark J. ; Bongiovanni, Marie N. ; Gras, Sally Louise ; Dewson, Grant ; Miller, Jason M.L. ; Finkbeiner, Steven ; Moily, Nagaraj S. ; Niclis, Jonathan ; Parish, Clare L. ; Purcell, Anthony W. ; Baker, Michael J ; Wilce, Jacqueline A. ; Waris, Saboora ; Stojanovski, Diana ; Böcking, Till ; Ang, Ching-Seng ; Ascher, David B ; Reid, Gavin E. ; Hatters, Danny M. / Huntingtin Inclusions Trigger Cellular Quiescence, Deactivate Apoptosis, and Lead to Delayed Necrosis. In: Cell Reports. 2017 ; Vol. 19, No. 5. pp. 919-927.
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title = "Huntingtin Inclusions Trigger Cellular Quiescence, Deactivate Apoptosis, and Lead to Delayed Necrosis",
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 = "flow cytometry, Huntington's disease, P bodies, ribosome quality control, RNA granule, stress granule, translation",
author = "Ramdzan, {Yasmin M.} and Trubetskov, {Mikhail M.} and Ormsby, {Angelique R} and Newcombe, {Estella A.} and Xiaojing Sui and Tobin, {Mark J.} and Bongiovanni, {Marie N.} and Gras, {Sally Louise} and Grant Dewson and Miller, {Jason M.L.} and Steven Finkbeiner and Moily, {Nagaraj S.} and Jonathan Niclis and Parish, {Clare L.} and Purcell, {Anthony W.} and Baker, {Michael J} and Wilce, {Jacqueline A.} and Saboora Waris and Diana Stojanovski and Till B{\"o}cking and Ching-Seng Ang and Ascher, {David B} and Reid, {Gavin E.} and Hatters, {Danny M.}",
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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, Böcking, T, Ang, C-S, Ascher, DB, Reid, GE & Hatters, DM 2017, 'Huntingtin Inclusions Trigger Cellular Quiescence, Deactivate Apoptosis, and Lead to Delayed Necrosis', Cell Reports, vol. 19, no. 5, pp. 919-927. https://doi.org/10.1016/j.celrep.2017.04.029

Huntingtin Inclusions Trigger Cellular Quiescence, Deactivate Apoptosis, and Lead to Delayed Necrosis. / Ramdzan, Yasmin M.; Trubetskov, Mikhail M.; Ormsby, Angelique R; Newcombe, Estella A.; Sui, Xiaojing; Tobin, Mark J.; Bongiovanni, Marie N.; Gras, Sally Louise; Dewson, Grant; Miller, Jason M.L.; Finkbeiner, Steven; Moily, Nagaraj S.; Niclis, Jonathan; Parish, Clare L.; Purcell, Anthony W.; Baker, Michael J; Wilce, Jacqueline A.; Waris, Saboora; Stojanovski, Diana; Böcking, Till; Ang, Ching-Seng; Ascher, David B; Reid, Gavin E.; Hatters, Danny M.

In: Cell Reports, Vol. 19, No. 5, 02.05.2017, p. 919-927.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Huntingtin Inclusions Trigger Cellular Quiescence, Deactivate Apoptosis, and Lead to Delayed Necrosis

AU - Ramdzan, Yasmin M.

AU - Trubetskov, Mikhail M.

AU - Ormsby, Angelique R

AU - Newcombe, Estella A.

AU - Sui, Xiaojing

AU - Tobin, Mark J.

AU - Bongiovanni, Marie N.

AU - Gras, Sally Louise

AU - Dewson, Grant

AU - Miller, Jason M.L.

AU - Finkbeiner, Steven

AU - Moily, Nagaraj S.

AU - Niclis, Jonathan

AU - Parish, Clare L.

AU - Purcell, Anthony W.

AU - Baker, Michael J

AU - Wilce, Jacqueline A.

AU - Waris, Saboora

AU - Stojanovski, Diana

AU - Böcking, Till

AU - Ang, Ching-Seng

AU - Ascher, David B

AU - Reid, Gavin E.

AU - Hatters, Danny M.

PY - 2017/5/2

Y1 - 2017/5/2

N2 - 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.

AB - 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.

KW - flow cytometry

KW - Huntington's disease

KW - P bodies

KW - ribosome quality control

KW - RNA granule

KW - stress granule

KW - translation

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DO - 10.1016/j.celrep.2017.04.029

M3 - Article

VL - 19

SP - 919

EP - 927

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

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