ER stress and unfolded protein response in amyotrophic lateral sclerosis

Kohsuke Kanekura, Hiroaki Suzuki, Sadakazu Aiso, Masaaki Matsuoka

研究成果: Article

102 引用 (Scopus)

抄録

Several theories on the pathomechanism of amyotrophic lateral sclerosis (ALS) have been proposed: misfolded protein aggregates, mitochondrial dysfunction, increased glutamate toxicity, increased oxidative stress, disturbance of intracellular trafficking, and so on. In parallel, a number of drugs that have been developed to alleviate the putative key pathomechanism of ALS have been under clinical trials. Unfortunately, however, almost all studies have finished unsuccessfully. This fact indicates that the key ALS pathomechanism still remains a tough enigma. Recent studies with autopsied ALS patients and studies using mutant SOD1 (mSOD1) transgenic mice have suggested that endoplasmic reticulum (ER) stress-related toxicity may be a relevant ALS pathomechanism. Levels of ER stress-related proteins were upregulated in motor neurons in the spinal cords of ALS patients. It was also shown that mSOD1, translocated to the ER, caused ER stress in neurons in the spinal cord of mSOD1 transgenic mice. We recently reported that the newly identified ALS-causative gene, vesicle-associated membrane protein-associated protein B (VAPB), plays a pivotal role in unfolded protein response (UPR), a physiological reaction against ER stress. The ALS-linked P56S mutation in VAPB nullifies the function of VAPB, resulting in motoneuronal vulnerability to ER stress. In this review, we summarize recent advances in research on the ALS pathomechanism especially addressing the putative involvement of ER stress and UPR dysfunction.

元の言語English
ページ(範囲)81-89
ページ数9
ジャーナルMolecular Neurobiology
39
発行部数2
DOI
出版物ステータスPublished - 2009 4

Fingerprint

Unfolded Protein Response
Endoplasmic Reticulum Stress
Amyotrophic Lateral Sclerosis
Heat-Shock Proteins
R-SNARE Proteins
Transgenic Mice
Spinal Cord
Motor Neurons
Endoplasmic Reticulum
Glutamic Acid
Oxidative Stress
Clinical Trials
Neurons
Mutation

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

これを引用

ER stress and unfolded protein response in amyotrophic lateral sclerosis. / Kanekura, Kohsuke; Suzuki, Hiroaki; Aiso, Sadakazu; Matsuoka, Masaaki.

:: Molecular Neurobiology, 巻 39, 番号 2, 04.2009, p. 81-89.

研究成果: Article

Kanekura, Kohsuke ; Suzuki, Hiroaki ; Aiso, Sadakazu ; Matsuoka, Masaaki. / ER stress and unfolded protein response in amyotrophic lateral sclerosis. :: Molecular Neurobiology. 2009 ; 巻 39, 番号 2. pp. 81-89.
@article{ab70b64392ef45fda4b743d9edb59211,
title = "ER stress and unfolded protein response in amyotrophic lateral sclerosis",
abstract = "Several theories on the pathomechanism of amyotrophic lateral sclerosis (ALS) have been proposed: misfolded protein aggregates, mitochondrial dysfunction, increased glutamate toxicity, increased oxidative stress, disturbance of intracellular trafficking, and so on. In parallel, a number of drugs that have been developed to alleviate the putative key pathomechanism of ALS have been under clinical trials. Unfortunately, however, almost all studies have finished unsuccessfully. This fact indicates that the key ALS pathomechanism still remains a tough enigma. Recent studies with autopsied ALS patients and studies using mutant SOD1 (mSOD1) transgenic mice have suggested that endoplasmic reticulum (ER) stress-related toxicity may be a relevant ALS pathomechanism. Levels of ER stress-related proteins were upregulated in motor neurons in the spinal cords of ALS patients. It was also shown that mSOD1, translocated to the ER, caused ER stress in neurons in the spinal cord of mSOD1 transgenic mice. We recently reported that the newly identified ALS-causative gene, vesicle-associated membrane protein-associated protein B (VAPB), plays a pivotal role in unfolded protein response (UPR), a physiological reaction against ER stress. The ALS-linked P56S mutation in VAPB nullifies the function of VAPB, resulting in motoneuronal vulnerability to ER stress. In this review, we summarize recent advances in research on the ALS pathomechanism especially addressing the putative involvement of ER stress and UPR dysfunction.",
keywords = "Amyotrophic lateral sclerosis, ER stress, Unfolded protein response",
author = "Kohsuke Kanekura and Hiroaki Suzuki and Sadakazu Aiso and Masaaki Matsuoka",
year = "2009",
month = "4",
doi = "10.1007/s12035-009-8054-3",
language = "English",
volume = "39",
pages = "81--89",
journal = "Molecular Neurobiology",
issn = "0893-7648",
publisher = "Humana Press",
number = "2",

}

TY - JOUR

T1 - ER stress and unfolded protein response in amyotrophic lateral sclerosis

AU - Kanekura, Kohsuke

AU - Suzuki, Hiroaki

AU - Aiso, Sadakazu

AU - Matsuoka, Masaaki

PY - 2009/4

Y1 - 2009/4

N2 - Several theories on the pathomechanism of amyotrophic lateral sclerosis (ALS) have been proposed: misfolded protein aggregates, mitochondrial dysfunction, increased glutamate toxicity, increased oxidative stress, disturbance of intracellular trafficking, and so on. In parallel, a number of drugs that have been developed to alleviate the putative key pathomechanism of ALS have been under clinical trials. Unfortunately, however, almost all studies have finished unsuccessfully. This fact indicates that the key ALS pathomechanism still remains a tough enigma. Recent studies with autopsied ALS patients and studies using mutant SOD1 (mSOD1) transgenic mice have suggested that endoplasmic reticulum (ER) stress-related toxicity may be a relevant ALS pathomechanism. Levels of ER stress-related proteins were upregulated in motor neurons in the spinal cords of ALS patients. It was also shown that mSOD1, translocated to the ER, caused ER stress in neurons in the spinal cord of mSOD1 transgenic mice. We recently reported that the newly identified ALS-causative gene, vesicle-associated membrane protein-associated protein B (VAPB), plays a pivotal role in unfolded protein response (UPR), a physiological reaction against ER stress. The ALS-linked P56S mutation in VAPB nullifies the function of VAPB, resulting in motoneuronal vulnerability to ER stress. In this review, we summarize recent advances in research on the ALS pathomechanism especially addressing the putative involvement of ER stress and UPR dysfunction.

AB - Several theories on the pathomechanism of amyotrophic lateral sclerosis (ALS) have been proposed: misfolded protein aggregates, mitochondrial dysfunction, increased glutamate toxicity, increased oxidative stress, disturbance of intracellular trafficking, and so on. In parallel, a number of drugs that have been developed to alleviate the putative key pathomechanism of ALS have been under clinical trials. Unfortunately, however, almost all studies have finished unsuccessfully. This fact indicates that the key ALS pathomechanism still remains a tough enigma. Recent studies with autopsied ALS patients and studies using mutant SOD1 (mSOD1) transgenic mice have suggested that endoplasmic reticulum (ER) stress-related toxicity may be a relevant ALS pathomechanism. Levels of ER stress-related proteins were upregulated in motor neurons in the spinal cords of ALS patients. It was also shown that mSOD1, translocated to the ER, caused ER stress in neurons in the spinal cord of mSOD1 transgenic mice. We recently reported that the newly identified ALS-causative gene, vesicle-associated membrane protein-associated protein B (VAPB), plays a pivotal role in unfolded protein response (UPR), a physiological reaction against ER stress. The ALS-linked P56S mutation in VAPB nullifies the function of VAPB, resulting in motoneuronal vulnerability to ER stress. In this review, we summarize recent advances in research on the ALS pathomechanism especially addressing the putative involvement of ER stress and UPR dysfunction.

KW - Amyotrophic lateral sclerosis

KW - ER stress

KW - Unfolded protein response

UR - http://www.scopus.com/inward/record.url?scp=66149156941&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66149156941&partnerID=8YFLogxK

U2 - 10.1007/s12035-009-8054-3

DO - 10.1007/s12035-009-8054-3

M3 - Article

C2 - 19184563

AN - SCOPUS:66149156941

VL - 39

SP - 81

EP - 89

JO - Molecular Neurobiology

JF - Molecular Neurobiology

SN - 0893-7648

IS - 2

ER -