Familial Alzheimer's disease mutations in presenilins: Effects on endoplasmic reticulum calcium homeostasis and correlation with clinical phenotypes

Omar Nelson, Charlene Supnet, Huarui Liu, Ilya Bezprozvanny

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Mutations in presenilins 1 and 2 (PS1 and PS2) are responsible for approximately 40% of all early onset familial Alzheimer's disease (FAD) monogenic cases. Presenilins (PSs) function as the catalytic subunit of γ-secretase and support cleavage of the amyloid-β protein precursor (AβPP). We previously discovered that PSs also function as passive endoplasmic reticulum (ER) calcium (Ca2+) leak channels and that most FAD mutations in PSs affected their ER Ca2+ leak function. To further validate the relevance of our findings to human disease, we here performed Ca2+ imaging experiments with lymphoblasts established from FAD patients. We discovered that most FAD mutations in PSs disrupted ER Ca 2+ leak function and resulted in increased ER Ca2+ pool in human lymphoblasts. However, we found that a subset of PS1 FAD mutants supported ER Ca2+ leak activity, as ER Ca2+ pool was unaffected in lymphoblasts. Most of the "functional" mutations for ER Ca2+ leak were clustered in the exon 8-9 area of PSEN1 gene and segregated with the cotton wool plaques and spastic paraparesis clinical phenotype occasionally observed in PS1 FAD patients. Our findings with the "functional" and "non-functional" PS1 FAD mutants were confirmed in Ca2+ rescue experiments with PS double-knockout mouse embryonic fibroblasts. Based on the combined effects of the PS1 FAD mutations on ER Ca2+ leak and γ-secretase activities we propose a model that explains the heterogeneity observed in FAD. The proposed model has implications for understanding the pathogenesis of both familial and sporadic AD.

Original languageEnglish (US)
Pages (from-to)781-793
Number of pages13
JournalJournal of Alzheimer's Disease
Volume21
Issue number3
DOIs
StatePublished - 2010

Fingerprint

Presenilins
Endoplasmic Reticulum
Alzheimer Disease
Homeostasis
Calcium
Phenotype
Mutation
Amyloid Precursor Protein Secretases
Presenilin-2
Spastic Paraparesis
Presenilin-1
Wool
Amyloid beta-Protein Precursor
Knockout Mice
Exons
Catalytic Domain
Fibroblasts

Keywords

  • Alzheimer's disease
  • amyloid-β
  • calcium
  • cotton wool plaques
  • endoplasmic reticulum
  • lymphoblasts
  • presenilins
  • spastic paraparesis

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

Cite this

@article{03d1daad5fbf41c8a1e7cd259a99a8d5,
title = "Familial Alzheimer's disease mutations in presenilins: Effects on endoplasmic reticulum calcium homeostasis and correlation with clinical phenotypes",
abstract = "Mutations in presenilins 1 and 2 (PS1 and PS2) are responsible for approximately 40{\%} of all early onset familial Alzheimer's disease (FAD) monogenic cases. Presenilins (PSs) function as the catalytic subunit of γ-secretase and support cleavage of the amyloid-β protein precursor (AβPP). We previously discovered that PSs also function as passive endoplasmic reticulum (ER) calcium (Ca2+) leak channels and that most FAD mutations in PSs affected their ER Ca2+ leak function. To further validate the relevance of our findings to human disease, we here performed Ca2+ imaging experiments with lymphoblasts established from FAD patients. We discovered that most FAD mutations in PSs disrupted ER Ca 2+ leak function and resulted in increased ER Ca2+ pool in human lymphoblasts. However, we found that a subset of PS1 FAD mutants supported ER Ca2+ leak activity, as ER Ca2+ pool was unaffected in lymphoblasts. Most of the {"}functional{"} mutations for ER Ca2+ leak were clustered in the exon 8-9 area of PSEN1 gene and segregated with the cotton wool plaques and spastic paraparesis clinical phenotype occasionally observed in PS1 FAD patients. Our findings with the {"}functional{"} and {"}non-functional{"} PS1 FAD mutants were confirmed in Ca2+ rescue experiments with PS double-knockout mouse embryonic fibroblasts. Based on the combined effects of the PS1 FAD mutations on ER Ca2+ leak and γ-secretase activities we propose a model that explains the heterogeneity observed in FAD. The proposed model has implications for understanding the pathogenesis of both familial and sporadic AD.",
keywords = "Alzheimer's disease, amyloid-β, calcium, cotton wool plaques, endoplasmic reticulum, lymphoblasts, presenilins, spastic paraparesis",
author = "Omar Nelson and Charlene Supnet and Huarui Liu and Ilya Bezprozvanny",
year = "2010",
doi = "10.3233/JAD-2010-100159",
language = "English (US)",
volume = "21",
pages = "781--793",
journal = "Journal of Alzheimer's Disease",
issn = "1387-2877",
publisher = "IOS Press",
number = "3",

}

TY - JOUR

T1 - Familial Alzheimer's disease mutations in presenilins

T2 - Effects on endoplasmic reticulum calcium homeostasis and correlation with clinical phenotypes

AU - Nelson, Omar

AU - Supnet, Charlene

AU - Liu, Huarui

AU - Bezprozvanny, Ilya

PY - 2010

Y1 - 2010

N2 - Mutations in presenilins 1 and 2 (PS1 and PS2) are responsible for approximately 40% of all early onset familial Alzheimer's disease (FAD) monogenic cases. Presenilins (PSs) function as the catalytic subunit of γ-secretase and support cleavage of the amyloid-β protein precursor (AβPP). We previously discovered that PSs also function as passive endoplasmic reticulum (ER) calcium (Ca2+) leak channels and that most FAD mutations in PSs affected their ER Ca2+ leak function. To further validate the relevance of our findings to human disease, we here performed Ca2+ imaging experiments with lymphoblasts established from FAD patients. We discovered that most FAD mutations in PSs disrupted ER Ca 2+ leak function and resulted in increased ER Ca2+ pool in human lymphoblasts. However, we found that a subset of PS1 FAD mutants supported ER Ca2+ leak activity, as ER Ca2+ pool was unaffected in lymphoblasts. Most of the "functional" mutations for ER Ca2+ leak were clustered in the exon 8-9 area of PSEN1 gene and segregated with the cotton wool plaques and spastic paraparesis clinical phenotype occasionally observed in PS1 FAD patients. Our findings with the "functional" and "non-functional" PS1 FAD mutants were confirmed in Ca2+ rescue experiments with PS double-knockout mouse embryonic fibroblasts. Based on the combined effects of the PS1 FAD mutations on ER Ca2+ leak and γ-secretase activities we propose a model that explains the heterogeneity observed in FAD. The proposed model has implications for understanding the pathogenesis of both familial and sporadic AD.

AB - Mutations in presenilins 1 and 2 (PS1 and PS2) are responsible for approximately 40% of all early onset familial Alzheimer's disease (FAD) monogenic cases. Presenilins (PSs) function as the catalytic subunit of γ-secretase and support cleavage of the amyloid-β protein precursor (AβPP). We previously discovered that PSs also function as passive endoplasmic reticulum (ER) calcium (Ca2+) leak channels and that most FAD mutations in PSs affected their ER Ca2+ leak function. To further validate the relevance of our findings to human disease, we here performed Ca2+ imaging experiments with lymphoblasts established from FAD patients. We discovered that most FAD mutations in PSs disrupted ER Ca 2+ leak function and resulted in increased ER Ca2+ pool in human lymphoblasts. However, we found that a subset of PS1 FAD mutants supported ER Ca2+ leak activity, as ER Ca2+ pool was unaffected in lymphoblasts. Most of the "functional" mutations for ER Ca2+ leak were clustered in the exon 8-9 area of PSEN1 gene and segregated with the cotton wool plaques and spastic paraparesis clinical phenotype occasionally observed in PS1 FAD patients. Our findings with the "functional" and "non-functional" PS1 FAD mutants were confirmed in Ca2+ rescue experiments with PS double-knockout mouse embryonic fibroblasts. Based on the combined effects of the PS1 FAD mutations on ER Ca2+ leak and γ-secretase activities we propose a model that explains the heterogeneity observed in FAD. The proposed model has implications for understanding the pathogenesis of both familial and sporadic AD.

KW - Alzheimer's disease

KW - amyloid-β

KW - calcium

KW - cotton wool plaques

KW - endoplasmic reticulum

KW - lymphoblasts

KW - presenilins

KW - spastic paraparesis

UR - http://www.scopus.com/inward/record.url?scp=77954129392&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954129392&partnerID=8YFLogxK

U2 - 10.3233/JAD-2010-100159

DO - 10.3233/JAD-2010-100159

M3 - Article

C2 - 20634584

AN - SCOPUS:77954129392

VL - 21

SP - 781

EP - 793

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

IS - 3

ER -