The unfolded protein response in models of human mutant G93A amyotrophic lateral sclerosis

T. Prell, J. Lautenschläger, O. W. Witte, M. T. Carri, J. Grosskreutz

Research output: Contribution to journalArticle

Abstract

Recent studies indicate that endoplasmic reticulum (ER) stress is involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS). ER stress occurs when the ER-mitochondria calcium cycle (ERMCC) is disturbed and misfolded proteins accumulate in the ER. To cope with ER stress, the cell engages the unfolded protein response (UPR). While activation of the UPR has been shown in some ALS models and tissues, ER stress elements have not been studied directly in motor neurons. Here we investigated the expression of XBP1 and ATF6α and phosphorylation of eIF2α, and their modulation, in mutated SOD1 G93A NSC34 and animal model of ALS. Expression of XBP1 and ATF6α mRNA and protein was enhanced in SOD1 G93A NSC34 cells. Activation of ATF6α and XBP1 and phosphorylation of eIF2α were detectable in mutated SOD1 G93A motor but not in wild-type motor neurons. Treatment with the ER stressor thapsigargin enhanced phosphorylation of eIF2α and activated proteolysis of ATF6α and splicing of XBP1 in NSC34 and motor neurons in a time-dependent manner. The present study thus provides direct evidence of activated UPR in motor neurons which overexpress human pathogenic mutant SOD1 G93A, providing evidence that ER stress plays a major role in ALS.

Original languageEnglish
Pages (from-to)652-660
Number of pages9
JournalEuropean Journal of Neuroscience
Volume35
Issue number5
DOIs
Publication statusPublished - Mar 2012

Fingerprint

Unfolded Protein Response
Endoplasmic Reticulum Stress
Amyotrophic Lateral Sclerosis
Motor Neurons
Endoplasmic Reticulum
Phosphorylation
Thapsigargin
Proteolysis
Mitochondria
Proteins
Animal Models
Calcium
Messenger RNA

Keywords

  • Endoplasmic reticulum stress
  • Motor neuron
  • Superoxide dismutase
  • Unfolded protein response

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

The unfolded protein response in models of human mutant G93A amyotrophic lateral sclerosis. / Prell, T.; Lautenschläger, J.; Witte, O. W.; Carri, M. T.; Grosskreutz, J.

In: European Journal of Neuroscience, Vol. 35, No. 5, 03.2012, p. 652-660.

Research output: Contribution to journalArticle

Prell, T. ; Lautenschläger, J. ; Witte, O. W. ; Carri, M. T. ; Grosskreutz, J. / The unfolded protein response in models of human mutant G93A amyotrophic lateral sclerosis. In: European Journal of Neuroscience. 2012 ; Vol. 35, No. 5. pp. 652-660.
@article{17f602a35abb42f6a5830b70c49af6e4,
title = "The unfolded protein response in models of human mutant G93A amyotrophic lateral sclerosis",
abstract = "Recent studies indicate that endoplasmic reticulum (ER) stress is involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS). ER stress occurs when the ER-mitochondria calcium cycle (ERMCC) is disturbed and misfolded proteins accumulate in the ER. To cope with ER stress, the cell engages the unfolded protein response (UPR). While activation of the UPR has been shown in some ALS models and tissues, ER stress elements have not been studied directly in motor neurons. Here we investigated the expression of XBP1 and ATF6α and phosphorylation of eIF2α, and their modulation, in mutated SOD1 G93A NSC34 and animal model of ALS. Expression of XBP1 and ATF6α mRNA and protein was enhanced in SOD1 G93A NSC34 cells. Activation of ATF6α and XBP1 and phosphorylation of eIF2α were detectable in mutated SOD1 G93A motor but not in wild-type motor neurons. Treatment with the ER stressor thapsigargin enhanced phosphorylation of eIF2α and activated proteolysis of ATF6α and splicing of XBP1 in NSC34 and motor neurons in a time-dependent manner. The present study thus provides direct evidence of activated UPR in motor neurons which overexpress human pathogenic mutant SOD1 G93A, providing evidence that ER stress plays a major role in ALS.",
keywords = "Endoplasmic reticulum stress, Motor neuron, Superoxide dismutase, Unfolded protein response",
author = "T. Prell and J. Lautenschl{\"a}ger and Witte, {O. W.} and Carri, {M. T.} and J. Grosskreutz",
year = "2012",
month = "3",
doi = "10.1111/j.1460-9568.2012.08008.x",
language = "English",
volume = "35",
pages = "652--660",
journal = "European Journal of Neuroscience",
issn = "0953-816X",
publisher = "Wiley-Blackwell",
number = "5",

}

TY - JOUR

T1 - The unfolded protein response in models of human mutant G93A amyotrophic lateral sclerosis

AU - Prell, T.

AU - Lautenschläger, J.

AU - Witte, O. W.

AU - Carri, M. T.

AU - Grosskreutz, J.

PY - 2012/3

Y1 - 2012/3

N2 - Recent studies indicate that endoplasmic reticulum (ER) stress is involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS). ER stress occurs when the ER-mitochondria calcium cycle (ERMCC) is disturbed and misfolded proteins accumulate in the ER. To cope with ER stress, the cell engages the unfolded protein response (UPR). While activation of the UPR has been shown in some ALS models and tissues, ER stress elements have not been studied directly in motor neurons. Here we investigated the expression of XBP1 and ATF6α and phosphorylation of eIF2α, and their modulation, in mutated SOD1 G93A NSC34 and animal model of ALS. Expression of XBP1 and ATF6α mRNA and protein was enhanced in SOD1 G93A NSC34 cells. Activation of ATF6α and XBP1 and phosphorylation of eIF2α were detectable in mutated SOD1 G93A motor but not in wild-type motor neurons. Treatment with the ER stressor thapsigargin enhanced phosphorylation of eIF2α and activated proteolysis of ATF6α and splicing of XBP1 in NSC34 and motor neurons in a time-dependent manner. The present study thus provides direct evidence of activated UPR in motor neurons which overexpress human pathogenic mutant SOD1 G93A, providing evidence that ER stress plays a major role in ALS.

AB - Recent studies indicate that endoplasmic reticulum (ER) stress is involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS). ER stress occurs when the ER-mitochondria calcium cycle (ERMCC) is disturbed and misfolded proteins accumulate in the ER. To cope with ER stress, the cell engages the unfolded protein response (UPR). While activation of the UPR has been shown in some ALS models and tissues, ER stress elements have not been studied directly in motor neurons. Here we investigated the expression of XBP1 and ATF6α and phosphorylation of eIF2α, and their modulation, in mutated SOD1 G93A NSC34 and animal model of ALS. Expression of XBP1 and ATF6α mRNA and protein was enhanced in SOD1 G93A NSC34 cells. Activation of ATF6α and XBP1 and phosphorylation of eIF2α were detectable in mutated SOD1 G93A motor but not in wild-type motor neurons. Treatment with the ER stressor thapsigargin enhanced phosphorylation of eIF2α and activated proteolysis of ATF6α and splicing of XBP1 in NSC34 and motor neurons in a time-dependent manner. The present study thus provides direct evidence of activated UPR in motor neurons which overexpress human pathogenic mutant SOD1 G93A, providing evidence that ER stress plays a major role in ALS.

KW - Endoplasmic reticulum stress

KW - Motor neuron

KW - Superoxide dismutase

KW - Unfolded protein response

UR - http://www.scopus.com/inward/record.url?scp=84857953079&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84857953079&partnerID=8YFLogxK

U2 - 10.1111/j.1460-9568.2012.08008.x

DO - 10.1111/j.1460-9568.2012.08008.x

M3 - Article

C2 - 22390177

AN - SCOPUS:84857953079

VL - 35

SP - 652

EP - 660

JO - European Journal of Neuroscience

JF - European Journal of Neuroscience

SN - 0953-816X

IS - 5

ER -