Repression of transcription of presenilin-1 inhibits γ-secretase independent ER Ca²⁺ leak that is impaired by FAD mutations

J Neurochem. 2012 Aug;122(3):487-500. doi: 10.1111/j.1471-4159.2012.07794.x. Epub 2012 Jun 22.


Genetic deletion or mutations of presenilin genes (PS1/PS2) cause familial Alzheimer's disease and calcium (Ca²⁺) signaling abnormalities. PS1/PS2 act as endoplasmic reticulum (ER) Ca²⁺ leak channels that facilitate passive Ca²⁺ leak across ER membrane. Studies with PS1/PS2 double knockout (PS1/PS2-DKO) mouse embryonic fibroblasts showed that PS1/PS2 were responsible for 80% of passive Ca²⁺ leak from the lumen of endoplasmic reticulum to cytosol. Transient transfection of the wild type PS1 expression construct increased cytoplasmic Ca²⁺ as a result of Ca²⁺ leak across ER membrane whereas the FADPS1 (PS1-M146V) mutation construct alone or in combination with the wild type PS1 expression construct abrogated Ca²⁺ leak in SK-N-SH cells. Inhibition of basal c-jun-NH2-terminal kinase (JNK) activity by JNK inhibitor SP600125 repressed PS1 transcription and PS1 protein expression by augmenting p53 protein level in SK-N-SH cells (Lee and Das 2008). In this report we also showed that repression of PS1 transcription by JNK inhibitor SP600125 inhibited passive Ca²⁺ leak across ER membrane which could be rescued by expressing PS1 wild type and not by expressing FADPS1 (PS1-M146V) under a SP600125 non-responsive promoter. Treatment of SK-N-SH cells with SP600125 also triggered InsP3R-mediated Ca²⁺ release from the ER by addition of 500 nM bradykinin, an agonist of InsP3 receptor (InsP3R1) without changing the expression of InsP3R1. This data confirms that SP600125 increases the Ca²⁺ store in the ER by inhibiting PS1-mediated Ca²⁺ leak across ER membrane. p53, ZNF237 and Chromodomain helicase DNA-binding protein 3 which are repressors of PS1 transcription, also reduced Ca²⁺ leak across ER membrane in SK-N-SH cells but γ-secretase inhibitor or dominant negative γ-secretase-specific PS1 mutant (PS1-D257A) had no significant effect. Therefore, p53, ZNF237, and Chromodomain helicase DNA-binding protein 3 inhibit the function ER Ca²⁺ leak channels to regulate both ER and cytoplasmic Ca²⁺ levels and may potentially control Ca²⁺-signaling function of PS1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Anthracenes / pharmacology
  • Calcium / metabolism*
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Cytosol / drug effects
  • Cytosol / metabolism
  • DNA Helicases / metabolism
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Methionine / genetics
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex
  • Mutation / genetics*
  • Neuroblastoma / pathology
  • Neuroblastoma / ultrastructure
  • Nuclear Proteins / metabolism
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Presenilin-1 / genetics*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Statistics, Nonparametric
  • Thapsigargin / pharmacology
  • Transfection
  • Valine / genetics


  • Anthracenes
  • Carrier Proteins
  • Enzyme Inhibitors
  • Inositol 1,4,5-Trisphosphate Receptors
  • Nuclear Proteins
  • Peptide Fragments
  • Presenilin-1
  • ZMYM5 protein, human
  • pyrazolanthrone
  • Thapsigargin
  • Methionine
  • Amyloid Precursor Protein Secretases
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex
  • DNA Helicases
  • CHD3 protein, human
  • Valine
  • Calcium