Fibroblasts from FAD-linked presenilin 1 mutations display a normal unfolded protein response but overproduce Aβ42 in response to tunicamycin

Alessandra Piccini, Anna Fassio, Elena Pasqualetto, Antonella Vitali, Roberta Borghi, Daniela Palmieri, Benedetta Nacmias, Sandro Sorbi, Roberto Sitia, Massimo Tabaton

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Many patients affected by early onset familial Alzheimer's disease (FAD), carry mutations in the presenilin 1 (PS1) gene. Since it has been suggested that FAD-linked PS1 mutations impair the unfolded protein response (UPR) due to endoplasmic reticulum (ER) stress, we analyzed the UPR and amyloid β-protein processing in fibroblasts bearing various PS1 mutations. Neither in normal conditions nor after induction of ER stress with DTT or tunicamycin were the mRNA levels of UPR-responsive genes (BiP and PDI) significantly different in control and FAD fibroblasts. DTT, which blocked APP transport to the Golgi, caused a 30% decrease of secreted Aβ42 in wild type and PS1 mutant fibroblasts. In contrast, tunicamycin, which allowed exit of APP from the ER, increased secreted Aβ42 only in PS1 mutant fibroblasts. Our findings suggest that, although the UPR is active in fibroblasts from FAD patients, mutant PS1 may selectively increase Aβ42 secretion when N-glycosylation is impaired.

Original languageEnglish
Pages (from-to)380-386
Number of pages7
JournalNeurobiology of Disease
Volume15
Issue number2
DOIs
Publication statusPublished - Mar 2004

Fingerprint

Presenilin-1
Unfolded Protein Response
Tunicamycin
Alzheimer Disease
Fibroblasts
Mutation
Endoplasmic Reticulum Stress
Amyloidogenic Proteins
Glycosylation
Endoplasmic Reticulum
Genes
Messenger RNA

Keywords

  • AD
  • Alzheimer's disease
  • Amyloid
  • Amyloid β-protein
  • APP
  • Endoplasmic reticulum
  • ER
  • Presenilin
  • Primary fibroblasts
  • PS
  • Unfolded protein response
  • Unfolding protein response
  • UPR

ASJC Scopus subject areas

  • Neurology

Cite this

Fibroblasts from FAD-linked presenilin 1 mutations display a normal unfolded protein response but overproduce Aβ42 in response to tunicamycin. / Piccini, Alessandra; Fassio, Anna; Pasqualetto, Elena; Vitali, Antonella; Borghi, Roberta; Palmieri, Daniela; Nacmias, Benedetta; Sorbi, Sandro; Sitia, Roberto; Tabaton, Massimo.

In: Neurobiology of Disease, Vol. 15, No. 2, 03.2004, p. 380-386.

Research output: Contribution to journalArticle

Piccini, A, Fassio, A, Pasqualetto, E, Vitali, A, Borghi, R, Palmieri, D, Nacmias, B, Sorbi, S, Sitia, R & Tabaton, M 2004, 'Fibroblasts from FAD-linked presenilin 1 mutations display a normal unfolded protein response but overproduce Aβ42 in response to tunicamycin', Neurobiology of Disease, vol. 15, no. 2, pp. 380-386. https://doi.org/10.1016/j.nbd.2003.11.013
Piccini, Alessandra ; Fassio, Anna ; Pasqualetto, Elena ; Vitali, Antonella ; Borghi, Roberta ; Palmieri, Daniela ; Nacmias, Benedetta ; Sorbi, Sandro ; Sitia, Roberto ; Tabaton, Massimo. / Fibroblasts from FAD-linked presenilin 1 mutations display a normal unfolded protein response but overproduce Aβ42 in response to tunicamycin. In: Neurobiology of Disease. 2004 ; Vol. 15, No. 2. pp. 380-386.
@article{33d31177848e4a22ad4d875e7c2ec1c7,
title = "Fibroblasts from FAD-linked presenilin 1 mutations display a normal unfolded protein response but overproduce Aβ42 in response to tunicamycin",
abstract = "Many patients affected by early onset familial Alzheimer's disease (FAD), carry mutations in the presenilin 1 (PS1) gene. Since it has been suggested that FAD-linked PS1 mutations impair the unfolded protein response (UPR) due to endoplasmic reticulum (ER) stress, we analyzed the UPR and amyloid β-protein processing in fibroblasts bearing various PS1 mutations. Neither in normal conditions nor after induction of ER stress with DTT or tunicamycin were the mRNA levels of UPR-responsive genes (BiP and PDI) significantly different in control and FAD fibroblasts. DTT, which blocked APP transport to the Golgi, caused a 30{\%} decrease of secreted Aβ42 in wild type and PS1 mutant fibroblasts. In contrast, tunicamycin, which allowed exit of APP from the ER, increased secreted Aβ42 only in PS1 mutant fibroblasts. Our findings suggest that, although the UPR is active in fibroblasts from FAD patients, mutant PS1 may selectively increase Aβ42 secretion when N-glycosylation is impaired.",
keywords = "Aβ, AD, Alzheimer's disease, Amyloid, Amyloid β-protein, APP, Endoplasmic reticulum, ER, Presenilin, Primary fibroblasts, PS, Unfolded protein response, Unfolding protein response, UPR",
author = "Alessandra Piccini and Anna Fassio and Elena Pasqualetto and Antonella Vitali and Roberta Borghi and Daniela Palmieri and Benedetta Nacmias and Sandro Sorbi and Roberto Sitia and Massimo Tabaton",
year = "2004",
month = "3",
doi = "10.1016/j.nbd.2003.11.013",
language = "English",
volume = "15",
pages = "380--386",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Fibroblasts from FAD-linked presenilin 1 mutations display a normal unfolded protein response but overproduce Aβ42 in response to tunicamycin

AU - Piccini, Alessandra

AU - Fassio, Anna

AU - Pasqualetto, Elena

AU - Vitali, Antonella

AU - Borghi, Roberta

AU - Palmieri, Daniela

AU - Nacmias, Benedetta

AU - Sorbi, Sandro

AU - Sitia, Roberto

AU - Tabaton, Massimo

PY - 2004/3

Y1 - 2004/3

N2 - Many patients affected by early onset familial Alzheimer's disease (FAD), carry mutations in the presenilin 1 (PS1) gene. Since it has been suggested that FAD-linked PS1 mutations impair the unfolded protein response (UPR) due to endoplasmic reticulum (ER) stress, we analyzed the UPR and amyloid β-protein processing in fibroblasts bearing various PS1 mutations. Neither in normal conditions nor after induction of ER stress with DTT or tunicamycin were the mRNA levels of UPR-responsive genes (BiP and PDI) significantly different in control and FAD fibroblasts. DTT, which blocked APP transport to the Golgi, caused a 30% decrease of secreted Aβ42 in wild type and PS1 mutant fibroblasts. In contrast, tunicamycin, which allowed exit of APP from the ER, increased secreted Aβ42 only in PS1 mutant fibroblasts. Our findings suggest that, although the UPR is active in fibroblasts from FAD patients, mutant PS1 may selectively increase Aβ42 secretion when N-glycosylation is impaired.

AB - Many patients affected by early onset familial Alzheimer's disease (FAD), carry mutations in the presenilin 1 (PS1) gene. Since it has been suggested that FAD-linked PS1 mutations impair the unfolded protein response (UPR) due to endoplasmic reticulum (ER) stress, we analyzed the UPR and amyloid β-protein processing in fibroblasts bearing various PS1 mutations. Neither in normal conditions nor after induction of ER stress with DTT or tunicamycin were the mRNA levels of UPR-responsive genes (BiP and PDI) significantly different in control and FAD fibroblasts. DTT, which blocked APP transport to the Golgi, caused a 30% decrease of secreted Aβ42 in wild type and PS1 mutant fibroblasts. In contrast, tunicamycin, which allowed exit of APP from the ER, increased secreted Aβ42 only in PS1 mutant fibroblasts. Our findings suggest that, although the UPR is active in fibroblasts from FAD patients, mutant PS1 may selectively increase Aβ42 secretion when N-glycosylation is impaired.

KW - Aβ

KW - AD

KW - Alzheimer's disease

KW - Amyloid

KW - Amyloid β-protein

KW - APP

KW - Endoplasmic reticulum

KW - ER

KW - Presenilin

KW - Primary fibroblasts

KW - PS

KW - Unfolded protein response

KW - Unfolding protein response

KW - UPR

UR - http://www.scopus.com/inward/record.url?scp=10744222838&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10744222838&partnerID=8YFLogxK

U2 - 10.1016/j.nbd.2003.11.013

DO - 10.1016/j.nbd.2003.11.013

M3 - Article

C2 - 15006708

AN - SCOPUS:10744222838

VL - 15

SP - 380

EP - 386

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

IS - 2

ER -