Exploring the Interaction Between eIF2α Dysregulation, Acute Endoplasmic Reticulum Stress and DYT1 Dystonia in the Mammalian Brain

Genevieve Beauvais, Noela Rodriguez-Losada, Lei Ying, Zuchra Zakirova, Jaime L. Watson, Benjamin Readhead, Paul Gadue, Deborah L. French, Michelle E. Ehrlich, Pedro Gonzalez-Alegre

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

DYT1 dystonia is a neurological disease caused by dominant mutations in the TOR1A gene, encoding for the endoplasmic reticulum (ER)-resident protein torsinA. Recent reports linked expression of the DYT1-causing protein with dysregulation of eIF2α a key component of the cellular response to ER stress known as the unfolded protein response (UPR). However, the response of the DYT1 mammalian brain to acute ER stress inducers has not been evaluated in vivo. We hypothesized that torsinA regulates the neuronal UPR and expression of its mutant form would alter this process. TorsinA was post-transcriptionally upregulated upon acute ER stress in different models, suggesting a role in this response. Moreover, increased basal phosphorylation of eIF2α in DYT1 transgenic rats was associated with an abnormal response to acute ER stress. Finally, an unbiased RNA-Seq-based transcriptomic analysis of embryonic brain tissue in heterozygous and homozygous DYT1 knockin mice confirmed the presence of eIF2α dysregulation in the DYT1 brain. In sum, these findings support previous reports linking torsinA function, eIF2α signaling and the neuronal response to ER stress in vivo. Furthermore, we describe novel protocols to investigate neuronal ER stress in cultured neurons and in vivo.

Original languageEnglish (US)
Pages (from-to)455-468
Number of pages14
JournalNeuroscience
Volume371
DOIs
StatePublished - Feb 10 2018
Externally publishedYes

Fingerprint

Endoplasmic Reticulum Stress
Dystonia
Brain
Unfolded Protein Response
Transgenic Rats
Endoplasmic Reticulum
Proteins
Phosphorylation
RNA
Neurons
Mutation
Genes

Keywords

  • dystonia
  • eif2α
  • ER stress
  • TorsinA
  • UPR

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Exploring the Interaction Between eIF2α Dysregulation, Acute Endoplasmic Reticulum Stress and DYT1 Dystonia in the Mammalian Brain. / Beauvais, Genevieve; Rodriguez-Losada, Noela; Ying, Lei; Zakirova, Zuchra; Watson, Jaime L.; Readhead, Benjamin; Gadue, Paul; French, Deborah L.; Ehrlich, Michelle E.; Gonzalez-Alegre, Pedro.

In: Neuroscience, Vol. 371, 10.02.2018, p. 455-468.

Research output: Contribution to journalArticle

Beauvais, G, Rodriguez-Losada, N, Ying, L, Zakirova, Z, Watson, JL, Readhead, B, Gadue, P, French, DL, Ehrlich, ME & Gonzalez-Alegre, P 2018, 'Exploring the Interaction Between eIF2α Dysregulation, Acute Endoplasmic Reticulum Stress and DYT1 Dystonia in the Mammalian Brain', Neuroscience, vol. 371, pp. 455-468. https://doi.org/10.1016/j.neuroscience.2017.12.033
Beauvais, Genevieve ; Rodriguez-Losada, Noela ; Ying, Lei ; Zakirova, Zuchra ; Watson, Jaime L. ; Readhead, Benjamin ; Gadue, Paul ; French, Deborah L. ; Ehrlich, Michelle E. ; Gonzalez-Alegre, Pedro. / Exploring the Interaction Between eIF2α Dysregulation, Acute Endoplasmic Reticulum Stress and DYT1 Dystonia in the Mammalian Brain. In: Neuroscience. 2018 ; Vol. 371. pp. 455-468.
@article{0e0987c39afa43fc8c0e1768fda232a6,
title = "Exploring the Interaction Between eIF2α Dysregulation, Acute Endoplasmic Reticulum Stress and DYT1 Dystonia in the Mammalian Brain",
abstract = "DYT1 dystonia is a neurological disease caused by dominant mutations in the TOR1A gene, encoding for the endoplasmic reticulum (ER)-resident protein torsinA. Recent reports linked expression of the DYT1-causing protein with dysregulation of eIF2α a key component of the cellular response to ER stress known as the unfolded protein response (UPR). However, the response of the DYT1 mammalian brain to acute ER stress inducers has not been evaluated in vivo. We hypothesized that torsinA regulates the neuronal UPR and expression of its mutant form would alter this process. TorsinA was post-transcriptionally upregulated upon acute ER stress in different models, suggesting a role in this response. Moreover, increased basal phosphorylation of eIF2α in DYT1 transgenic rats was associated with an abnormal response to acute ER stress. Finally, an unbiased RNA-Seq-based transcriptomic analysis of embryonic brain tissue in heterozygous and homozygous DYT1 knockin mice confirmed the presence of eIF2α dysregulation in the DYT1 brain. In sum, these findings support previous reports linking torsinA function, eIF2α signaling and the neuronal response to ER stress in vivo. Furthermore, we describe novel protocols to investigate neuronal ER stress in cultured neurons and in vivo.",
keywords = "dystonia, eif2α, ER stress, TorsinA, UPR",
author = "Genevieve Beauvais and Noela Rodriguez-Losada and Lei Ying and Zuchra Zakirova and Watson, {Jaime L.} and Benjamin Readhead and Paul Gadue and French, {Deborah L.} and Ehrlich, {Michelle E.} and Pedro Gonzalez-Alegre",
year = "2018",
month = "2",
day = "10",
doi = "10.1016/j.neuroscience.2017.12.033",
language = "English (US)",
volume = "371",
pages = "455--468",
journal = "Neuroscience",
issn = "0306-4522",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Exploring the Interaction Between eIF2α Dysregulation, Acute Endoplasmic Reticulum Stress and DYT1 Dystonia in the Mammalian Brain

AU - Beauvais, Genevieve

AU - Rodriguez-Losada, Noela

AU - Ying, Lei

AU - Zakirova, Zuchra

AU - Watson, Jaime L.

AU - Readhead, Benjamin

AU - Gadue, Paul

AU - French, Deborah L.

AU - Ehrlich, Michelle E.

AU - Gonzalez-Alegre, Pedro

PY - 2018/2/10

Y1 - 2018/2/10

N2 - DYT1 dystonia is a neurological disease caused by dominant mutations in the TOR1A gene, encoding for the endoplasmic reticulum (ER)-resident protein torsinA. Recent reports linked expression of the DYT1-causing protein with dysregulation of eIF2α a key component of the cellular response to ER stress known as the unfolded protein response (UPR). However, the response of the DYT1 mammalian brain to acute ER stress inducers has not been evaluated in vivo. We hypothesized that torsinA regulates the neuronal UPR and expression of its mutant form would alter this process. TorsinA was post-transcriptionally upregulated upon acute ER stress in different models, suggesting a role in this response. Moreover, increased basal phosphorylation of eIF2α in DYT1 transgenic rats was associated with an abnormal response to acute ER stress. Finally, an unbiased RNA-Seq-based transcriptomic analysis of embryonic brain tissue in heterozygous and homozygous DYT1 knockin mice confirmed the presence of eIF2α dysregulation in the DYT1 brain. In sum, these findings support previous reports linking torsinA function, eIF2α signaling and the neuronal response to ER stress in vivo. Furthermore, we describe novel protocols to investigate neuronal ER stress in cultured neurons and in vivo.

AB - DYT1 dystonia is a neurological disease caused by dominant mutations in the TOR1A gene, encoding for the endoplasmic reticulum (ER)-resident protein torsinA. Recent reports linked expression of the DYT1-causing protein with dysregulation of eIF2α a key component of the cellular response to ER stress known as the unfolded protein response (UPR). However, the response of the DYT1 mammalian brain to acute ER stress inducers has not been evaluated in vivo. We hypothesized that torsinA regulates the neuronal UPR and expression of its mutant form would alter this process. TorsinA was post-transcriptionally upregulated upon acute ER stress in different models, suggesting a role in this response. Moreover, increased basal phosphorylation of eIF2α in DYT1 transgenic rats was associated with an abnormal response to acute ER stress. Finally, an unbiased RNA-Seq-based transcriptomic analysis of embryonic brain tissue in heterozygous and homozygous DYT1 knockin mice confirmed the presence of eIF2α dysregulation in the DYT1 brain. In sum, these findings support previous reports linking torsinA function, eIF2α signaling and the neuronal response to ER stress in vivo. Furthermore, we describe novel protocols to investigate neuronal ER stress in cultured neurons and in vivo.

KW - dystonia

KW - eif2α

KW - ER stress

KW - TorsinA

KW - UPR

UR - http://www.scopus.com/inward/record.url?scp=85040372031&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040372031&partnerID=8YFLogxK

U2 - 10.1016/j.neuroscience.2017.12.033

DO - 10.1016/j.neuroscience.2017.12.033

M3 - Article

VL - 371

SP - 455

EP - 468

JO - Neuroscience

JF - Neuroscience

SN - 0306-4522

ER -