Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer's disease pathogenesis

Research output: Contribution to journalReview article

13 Scopus citations

Abstract

Alzheimer 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 majority of FAD cases. Presenilins function as catalytic subunit of γ-secretase involved in 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 result in 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. Our latest work on studies of ER Ca 2+ leak channel function of presenilins and implications of these findings for understanding AD pathogenesis are discussed in this article.

Original languageEnglish (US)
Pages (from-to)744-751
Number of pages8
JournalScience China Life Sciences
Volume54
Issue number8
DOIs
StatePublished - Aug 1 2011

Keywords

  • Alzheimer's disease
  • amyloid
  • calcium signaling
  • gamma-secretase
  • neurodegeneration
  • presenilins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Environmental Science(all)
  • Agricultural and Biological Sciences(all)

Fingerprint Dive into the research topics of 'Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer's disease pathogenesis'. Together they form a unique fingerprint.

  • Cite this