Presenilin-1 mutations sensitize neurons to DNA damage-induced death by a mechanism involving perturbed calcium homeostasis and activation of calpains and caspase-12

Sic L. Chan, Carsten Culmsee, Norman Haughey, Wolfram Klapper, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

Mutations in presenilin-1 (PS1) can cause early onset familial Alzheimer's disease (AD). Studies of cultured cells and mice expressing mutant PS1 suggest that PS1 mutations may promote neuronal dysfunction and degeneration by altering cellular calcium homeostasis. On the other hand, it has been suggested that age-related damage to DNA in neurons may be an important early event in the pathogenesis of AD. We now report that PC12 cells and primary hippocampal neurons expressing mutant PS1 exhibit increased sensitivity to death induced by DNA damage. The hypersensitivity to DNA damage is correlated with increased intracellular Ca2+ levels, induction of p53, upregulation of the Ca2+-dependent protease m-calpain, and mitochondrial membrane depolarization. Moreover, activation of caspase-12, an endoplasmic reticulum (ER)-associated caspase, is greatly increased in cells expressing mutant PS1. DNA damage-induced death of cells expressing mutant PS1 was attenuated by inhibitors of calpains I and II, by an intracellular Ca2+ chelator, by the protein synthesis inhibitor cycloheximide, and by a broad-spectrum caspase inhibitor, but not by an inhibitor of caspase-1. Agents that release Ca2+ from the ER increased the vulnerability of cells expressing mutant PS1 to DNA damage. By promoting ER-mediated apoptotic proteolytic cascades, PS1 mutations may sensitize neurons to DNA damage.

Original languageEnglish (US)
Pages (from-to)2-19
Number of pages18
JournalNeurobiology of Disease
Volume11
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Caspase 12
Presenilin-1
Calpain
DNA Damage
Homeostasis
Calcium
Neurons
Mutation
Endoplasmic Reticulum
Alzheimer Disease
Protein Synthesis Inhibitors
Caspase Inhibitors
PC12 Cells
Mitochondrial Membranes
Cycloheximide
Chelating Agents
Caspases
Cultured Cells
Hypersensitivity
Peptide Hydrolases

Keywords

  • Alzheimer's disease
  • Endoplasmic reticulum
  • Hippocampal neurons
  • PARP
  • Topoisomerase

ASJC Scopus subject areas

  • Neurology

Cite this

Presenilin-1 mutations sensitize neurons to DNA damage-induced death by a mechanism involving perturbed calcium homeostasis and activation of calpains and caspase-12. / Chan, Sic L.; Culmsee, Carsten; Haughey, Norman; Klapper, Wolfram; Mattson, Mark P.

In: Neurobiology of Disease, Vol. 11, No. 1, 2002, p. 2-19.

Research output: Contribution to journalArticle

@article{d746f84677cb4e7198749661147d110c,
title = "Presenilin-1 mutations sensitize neurons to DNA damage-induced death by a mechanism involving perturbed calcium homeostasis and activation of calpains and caspase-12",
abstract = "Mutations in presenilin-1 (PS1) can cause early onset familial Alzheimer's disease (AD). Studies of cultured cells and mice expressing mutant PS1 suggest that PS1 mutations may promote neuronal dysfunction and degeneration by altering cellular calcium homeostasis. On the other hand, it has been suggested that age-related damage to DNA in neurons may be an important early event in the pathogenesis of AD. We now report that PC12 cells and primary hippocampal neurons expressing mutant PS1 exhibit increased sensitivity to death induced by DNA damage. The hypersensitivity to DNA damage is correlated with increased intracellular Ca2+ levels, induction of p53, upregulation of the Ca2+-dependent protease m-calpain, and mitochondrial membrane depolarization. Moreover, activation of caspase-12, an endoplasmic reticulum (ER)-associated caspase, is greatly increased in cells expressing mutant PS1. DNA damage-induced death of cells expressing mutant PS1 was attenuated by inhibitors of calpains I and II, by an intracellular Ca2+ chelator, by the protein synthesis inhibitor cycloheximide, and by a broad-spectrum caspase inhibitor, but not by an inhibitor of caspase-1. Agents that release Ca2+ from the ER increased the vulnerability of cells expressing mutant PS1 to DNA damage. By promoting ER-mediated apoptotic proteolytic cascades, PS1 mutations may sensitize neurons to DNA damage.",
keywords = "Alzheimer's disease, Endoplasmic reticulum, Hippocampal neurons, PARP, Topoisomerase",
author = "Chan, {Sic L.} and Carsten Culmsee and Norman Haughey and Wolfram Klapper and Mattson, {Mark P.}",
year = "2002",
doi = "10.1006/nbdi.2002.0542",
language = "English (US)",
volume = "11",
pages = "2--19",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Presenilin-1 mutations sensitize neurons to DNA damage-induced death by a mechanism involving perturbed calcium homeostasis and activation of calpains and caspase-12

AU - Chan, Sic L.

AU - Culmsee, Carsten

AU - Haughey, Norman

AU - Klapper, Wolfram

AU - Mattson, Mark P.

PY - 2002

Y1 - 2002

N2 - Mutations in presenilin-1 (PS1) can cause early onset familial Alzheimer's disease (AD). Studies of cultured cells and mice expressing mutant PS1 suggest that PS1 mutations may promote neuronal dysfunction and degeneration by altering cellular calcium homeostasis. On the other hand, it has been suggested that age-related damage to DNA in neurons may be an important early event in the pathogenesis of AD. We now report that PC12 cells and primary hippocampal neurons expressing mutant PS1 exhibit increased sensitivity to death induced by DNA damage. The hypersensitivity to DNA damage is correlated with increased intracellular Ca2+ levels, induction of p53, upregulation of the Ca2+-dependent protease m-calpain, and mitochondrial membrane depolarization. Moreover, activation of caspase-12, an endoplasmic reticulum (ER)-associated caspase, is greatly increased in cells expressing mutant PS1. DNA damage-induced death of cells expressing mutant PS1 was attenuated by inhibitors of calpains I and II, by an intracellular Ca2+ chelator, by the protein synthesis inhibitor cycloheximide, and by a broad-spectrum caspase inhibitor, but not by an inhibitor of caspase-1. Agents that release Ca2+ from the ER increased the vulnerability of cells expressing mutant PS1 to DNA damage. By promoting ER-mediated apoptotic proteolytic cascades, PS1 mutations may sensitize neurons to DNA damage.

AB - Mutations in presenilin-1 (PS1) can cause early onset familial Alzheimer's disease (AD). Studies of cultured cells and mice expressing mutant PS1 suggest that PS1 mutations may promote neuronal dysfunction and degeneration by altering cellular calcium homeostasis. On the other hand, it has been suggested that age-related damage to DNA in neurons may be an important early event in the pathogenesis of AD. We now report that PC12 cells and primary hippocampal neurons expressing mutant PS1 exhibit increased sensitivity to death induced by DNA damage. The hypersensitivity to DNA damage is correlated with increased intracellular Ca2+ levels, induction of p53, upregulation of the Ca2+-dependent protease m-calpain, and mitochondrial membrane depolarization. Moreover, activation of caspase-12, an endoplasmic reticulum (ER)-associated caspase, is greatly increased in cells expressing mutant PS1. DNA damage-induced death of cells expressing mutant PS1 was attenuated by inhibitors of calpains I and II, by an intracellular Ca2+ chelator, by the protein synthesis inhibitor cycloheximide, and by a broad-spectrum caspase inhibitor, but not by an inhibitor of caspase-1. Agents that release Ca2+ from the ER increased the vulnerability of cells expressing mutant PS1 to DNA damage. By promoting ER-mediated apoptotic proteolytic cascades, PS1 mutations may sensitize neurons to DNA damage.

KW - Alzheimer's disease

KW - Endoplasmic reticulum

KW - Hippocampal neurons

KW - PARP

KW - Topoisomerase

UR - http://www.scopus.com/inward/record.url?scp=0036452908&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036452908&partnerID=8YFLogxK

U2 - 10.1006/nbdi.2002.0542

DO - 10.1006/nbdi.2002.0542

M3 - Article

C2 - 12460542

AN - SCOPUS:0036452908

VL - 11

SP - 2

EP - 19

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

IS - 1

ER -