Calbindin D28K blocks the proapoptotic actions of mutant presenilin 1

Reduced oxidative stress and preserved mitochondrial function

Qing Guo, Sylvia Christakos, Nic Robinson, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

Mutations in the presenilin 1 (PS-1) gene account for many cases of early-onset autosomal dominant inherited forms of Alzheimer's disease. Recent findings suggest that PS-1 mutations may sensitize neurons to apoptosis induced by trophic factor withdrawal and exposure to amyloid β-peptide (Aβ). We now report that overexpression of the calcium-binding protein calbindin D28k prevents apoptosis in cultured neural cells expressing mutant PS-1 (L286V and M146V missense mutations). Elevations of the intracellular Ca2+ concentration and generation of reactive oxygen species induced by Aβ, and potentiated by mutant PS-1, were suppressed in calbindin- overexpressing cells. Impairment of mitochondrial function by Aβ (which preceded apoptosis) was exacerbated by PS-1 mutations and was largely prevented by culbindin. These findings suggest that PS-1 mutations render neurons vulnerable to apoptosis by a mechanism involving destabilization of cellular calcium homeostasis, which leads to oxidative stress and mitochondrial dysfunction.

Original languageEnglish (US)
Pages (from-to)3227-3232
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number6
DOIs
StatePublished - Mar 17 1998
Externally publishedYes

Fingerprint

Calbindin 1
Presenilin-1
Oxidative Stress
Apoptosis
Mutation
Neurons
Calbindins
Calcium-Binding Proteins
Missense Mutation
Amyloid
Cultured Cells
Reactive Oxygen Species
Alzheimer Disease
Homeostasis
Calcium
Genes

Keywords

  • Alzheimer's disease
  • Amyloid
  • Calcium binding protein
  • Endoplasmic reticulum
  • Mitochondrial transmembrane potential

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Calbindin D28K blocks the proapoptotic actions of mutant presenilin 1 : Reduced oxidative stress and preserved mitochondrial function. / Guo, Qing; Christakos, Sylvia; Robinson, Nic; Mattson, Mark P.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 6, 17.03.1998, p. 3227-3232.

Research output: Contribution to journalArticle

@article{e2753baf21f74ab78d4aec27c68eda64,
title = "Calbindin D28K blocks the proapoptotic actions of mutant presenilin 1: Reduced oxidative stress and preserved mitochondrial function",
abstract = "Mutations in the presenilin 1 (PS-1) gene account for many cases of early-onset autosomal dominant inherited forms of Alzheimer's disease. Recent findings suggest that PS-1 mutations may sensitize neurons to apoptosis induced by trophic factor withdrawal and exposure to amyloid β-peptide (Aβ). We now report that overexpression of the calcium-binding protein calbindin D28k prevents apoptosis in cultured neural cells expressing mutant PS-1 (L286V and M146V missense mutations). Elevations of the intracellular Ca2+ concentration and generation of reactive oxygen species induced by Aβ, and potentiated by mutant PS-1, were suppressed in calbindin- overexpressing cells. Impairment of mitochondrial function by Aβ (which preceded apoptosis) was exacerbated by PS-1 mutations and was largely prevented by culbindin. These findings suggest that PS-1 mutations render neurons vulnerable to apoptosis by a mechanism involving destabilization of cellular calcium homeostasis, which leads to oxidative stress and mitochondrial dysfunction.",
keywords = "Alzheimer's disease, Amyloid, Calcium binding protein, Endoplasmic reticulum, Mitochondrial transmembrane potential",
author = "Qing Guo and Sylvia Christakos and Nic Robinson and Mattson, {Mark P.}",
year = "1998",
month = "3",
day = "17",
doi = "10.1073/pnas.95.6.3227",
language = "English (US)",
volume = "95",
pages = "3227--3232",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "6",

}

TY - JOUR

T1 - Calbindin D28K blocks the proapoptotic actions of mutant presenilin 1

T2 - Reduced oxidative stress and preserved mitochondrial function

AU - Guo, Qing

AU - Christakos, Sylvia

AU - Robinson, Nic

AU - Mattson, Mark P.

PY - 1998/3/17

Y1 - 1998/3/17

N2 - Mutations in the presenilin 1 (PS-1) gene account for many cases of early-onset autosomal dominant inherited forms of Alzheimer's disease. Recent findings suggest that PS-1 mutations may sensitize neurons to apoptosis induced by trophic factor withdrawal and exposure to amyloid β-peptide (Aβ). We now report that overexpression of the calcium-binding protein calbindin D28k prevents apoptosis in cultured neural cells expressing mutant PS-1 (L286V and M146V missense mutations). Elevations of the intracellular Ca2+ concentration and generation of reactive oxygen species induced by Aβ, and potentiated by mutant PS-1, were suppressed in calbindin- overexpressing cells. Impairment of mitochondrial function by Aβ (which preceded apoptosis) was exacerbated by PS-1 mutations and was largely prevented by culbindin. These findings suggest that PS-1 mutations render neurons vulnerable to apoptosis by a mechanism involving destabilization of cellular calcium homeostasis, which leads to oxidative stress and mitochondrial dysfunction.

AB - Mutations in the presenilin 1 (PS-1) gene account for many cases of early-onset autosomal dominant inherited forms of Alzheimer's disease. Recent findings suggest that PS-1 mutations may sensitize neurons to apoptosis induced by trophic factor withdrawal and exposure to amyloid β-peptide (Aβ). We now report that overexpression of the calcium-binding protein calbindin D28k prevents apoptosis in cultured neural cells expressing mutant PS-1 (L286V and M146V missense mutations). Elevations of the intracellular Ca2+ concentration and generation of reactive oxygen species induced by Aβ, and potentiated by mutant PS-1, were suppressed in calbindin- overexpressing cells. Impairment of mitochondrial function by Aβ (which preceded apoptosis) was exacerbated by PS-1 mutations and was largely prevented by culbindin. These findings suggest that PS-1 mutations render neurons vulnerable to apoptosis by a mechanism involving destabilization of cellular calcium homeostasis, which leads to oxidative stress and mitochondrial dysfunction.

KW - Alzheimer's disease

KW - Amyloid

KW - Calcium binding protein

KW - Endoplasmic reticulum

KW - Mitochondrial transmembrane potential

UR - http://www.scopus.com/inward/record.url?scp=0032539814&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032539814&partnerID=8YFLogxK

U2 - 10.1073/pnas.95.6.3227

DO - 10.1073/pnas.95.6.3227

M3 - Article

VL - 95

SP - 3227

EP - 3232

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 6

ER -