Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response

Nat Cell Biol. 1999 Dec;1(8):479-85. doi: 10.1038/70265.

Abstract

Missense mutations in the human presenilin-1 (PS1) gene, which is found on chromosome 14, cause early-onset familial Alzheimer's disease (FAD). FAD-linked PS1 variants alter proteolytic processing of the amyloid precursor protein and cause an increase in vulnerability to apoptosis induced by various cell stresses. However, the mechanisms responsible for these phenomena are not clear. Here we report that mutations in PS1 affect the unfolded-protein response (UPR), which responds to the increased amount of unfolded proteins that accumulate in the endoplasmic reticulum (ER) under conditions that cause ER stress. PS1 mutations also lead to decreased expression of GRP78/Bip, a molecular chaperone, present in the ER, that can enable protein folding. Interestingly, GRP78 levels are reduced in the brains of Alzheimer's disease patients. The downregulation of UPR signalling by PS1 mutations is caused by disturbed function of IRE1, which is the proximal sensor of conditions in the ER lumen. Overexpression of GRP78 in neuroblastoma cells bearing PS1 mutants almost completely restores resistance to ER stress to the level of cells expressing wild-type PS1. These results show that mutations in PS1 may increase vulnerability to ER stress by altering the UPR signalling pathway.

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Calcimycin / pharmacology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Death / drug effects
  • Cell Line
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Endoribonucleases
  • HSP70 Heat-Shock Proteins / metabolism
  • Heat-Shock Proteins*
  • Humans
  • Intracellular Membranes / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Mutation / genetics*
  • Neuroblastoma
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Phosphorylation
  • Presenilin-1
  • Protein Binding
  • Protein Denaturation
  • Protein Folding*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction* / drug effects
  • Transfection
  • Tunicamycin / pharmacology

Substances

  • Carrier Proteins
  • HSP70 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Membrane Proteins
  • Molecular Chaperones
  • PSEN1 protein, human
  • Presenilin-1
  • RNA, Messenger
  • glucose-regulated proteins
  • Tunicamycin
  • Calcimycin
  • ERN2 protein, human
  • Ern2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • molecular chaperone GRP78