Appoptosin is a novel pro-apoptotic protein and mediates cell death in neurodegeneration

J Neurosci. 2012 Oct 31;32(44):15565-76. doi: 10.1523/JNEUROSCI.3668-12.2012.

Abstract

Apoptosis is an essential cellular process in multiple diseases and a major pathway for neuronal death in neurodegeneration. The detailed signaling events/pathways leading to apoptosis, especially in neurons, require further elucidation. Here we identify a β-amyloid precursor protein (APP)-interacting protein, designated as appoptosin, whose levels are upregulated in brain samples from Alzheimer's disease and infarct patients, and in rodent stroke models, as well as in neurons treated with β-amyloid (Aβ) and glutamate. We further demonstrate that appoptosin induces reactive oxygen species release and intrinsic caspase-dependent apoptosis. The physiological function of appoptosin is to transport/exchange glycine/5-amino-levulinic acid across the mitochondrial membrane for heme synthesis. Downregulation of appoptosin prevents cell death and caspase activation caused by glutamate or Aβ insults. APP modulates appoptosin-mediated apoptosis through interaction with appoptosin. Our study identifies appoptosin as a crucial player in apoptosis and a novel pro-apoptotic protein involved in neuronal cell death, providing a possible new therapeutic target for neurodegenerative disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / pathology
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Annexin A5 / metabolism
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / physiology*
  • Brain Infarction / pathology
  • Caspases / physiology
  • Cell Death / genetics
  • Cell Death / physiology*
  • Cell Line, Tumor
  • Female
  • Genetic Complementation Test
  • Heme / biosynthesis
  • Humans
  • Immunohistochemistry
  • Male
  • Mice
  • Microscopy, Fluorescence
  • Mitochondria / metabolism
  • Nerve Degeneration / genetics
  • Nerve Degeneration / pathology*
  • Neurons / pathology
  • Neurons / physiology
  • Pregnancy
  • RNA Interference
  • Rats
  • Reactive Oxygen Species

Substances

  • Amyloid beta-Protein Precursor
  • Annexin A5
  • Apoptosis Regulatory Proteins
  • Reactive Oxygen Species
  • Heme
  • Caspases