Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease

Nat Med. 1998 Aug;4(8):957-62. doi: 10.1038/nm0898-957.

Abstract

Prostate apoptosis response-4 (Par-4) is a protein containing both a leucine zipper and a death domain that was isolated by differential screening for genes upregulated in prostate cancer cells undergoing apoptosis. Par-4 is expressed in the nervous system, where its function is unknown. In Alzheimer disease (AD), neurons may die by apoptosis, and amyloid beta-protein (A beta) may play a role in this. We report here that Par-4 expression is increased in vulnerable neurons in AD brain and is induced in cultured neurons undergoing apoptosis. Blockade of Par-4 expression or function prevented neuronal apoptosis induced by Ab and trophic factor withdrawal. Par-4 expression was enhanced, and mitochondrial dysfunction and apoptosis exacerbated, in cells expressing presenilin-1 mutations associated with early-onset inherited AD.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / biosynthesis
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Brain / metabolism
  • Brain / pathology*
  • Carrier Proteins / analysis
  • Carrier Proteins / biosynthesis*
  • Cells, Cultured
  • Embryo, Mammalian
  • Gene Expression Regulation
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Leucine Zippers
  • Male
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Mitochondria / metabolism
  • Mutagenesis, Site-Directed
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Neurons / cytology
  • Neurons / metabolism*
  • Neurons / pathology
  • Oligonucleotides, Antisense / pharmacology
  • PC12 Cells
  • Peptide Fragments / biosynthesis
  • Peptide Fragments / pharmacology
  • Point Mutation
  • Polymerase Chain Reaction
  • Presenilin-1
  • Prostatic Neoplasms / pathology
  • Rats

Substances

  • Amyloid beta-Peptides
  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Oligonucleotides, Antisense
  • PSEN1 protein, human
  • Peptide Fragments
  • Presenilin-1
  • amyloid beta-protein (1-42)
  • prostate apoptosis response-4 protein