Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and is at present, incurable. The accumulation of toxic amyloid-beta (Aβ) peptide aggregates in AD brain is thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline, an idea that underlies the 'amyloid hypothesis' of AD etiology in both the familal (FAD) and sporadic forms of the disease. Genetic mutations causing FAD also result in the dysregulation of neuronal calcium (Ca 2+) handling and may contribute to AD pathogenesis, an idea termed the 'calcium hypothesis' of AD. Mutations in presenilin proteins account for the majority of FAD cases. Presenilins function as catalytic subunits of γ-secretase involved in the generation of Aβ peptide. Recently, we discovered that presenilns function as low-conductance, passive ER Ca 2+ leak channels, independent of γ-secretase activity. We further discovered that many FAD mutations in presenilins results in the loss of ER Ca 2+ leak function activity and Ca 2+ overload in the ER. These results provided potential explanation for abnormal Ca 2+ signaling observed in FAD cells with mutations in presenilns. The implications of these findings for understanding AD pathogenesis are discussed in this article.

Original languageEnglish (US)
Pages (from-to)303-309
Number of pages7
JournalCell Calcium
Volume50
Issue number3
DOIs
StatePublished - Sep 2011

Fingerprint

Presenilins
Flavin-Adenine Dinucleotide
Alzheimer Disease
Calcium
Amyloid Precursor Protein Secretases
Mutation
Poisons
Amyloid beta-Peptides
Amyloid
Neurodegenerative Diseases
Catalytic Domain
Peptides
Brain

Keywords

  • Alzheimer's disease
  • Amyloid
  • Calcium
  • Cotton wool plaques
  • Gamma-secretase
  • Presenilin
  • SCAM
  • Structure-function

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis. / Supnet, Charlene; Bezprozvanny, Ilya.

In: Cell Calcium, Vol. 50, No. 3, 09.2011, p. 303-309.

Research output: Contribution to journalArticle

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