Fas/CD95 regulatory protein Faim2 is neuroprotective after transient brain ischemia

J Neurosci. 2011 Jan 5;31(1):225-33. doi: 10.1523/JNEUROSCI.2188-10.2011.

Abstract

Death receptor (DR) signaling has a major impact on the outcome of numerous neurological diseases, including ischemic stroke. DRs mediate not only cell death signals, but also proinflammatory responses and cell proliferation. Identification of regulatory proteins that control the switch between apoptotic and alternative DR signaling opens new therapeutic opportunities. Fas apoptotic inhibitory molecule 2 (Faim2) is an evolutionary conserved, neuron-specific inhibitor of Fas/CD95-mediated apoptosis. To investigate its role during development and in disease models, we generated Faim2-deficient mice. The ubiquitous null mutation displayed a viable and fertile phenotype without overt deficiencies. However, lack of Faim2 caused an increase in susceptibility to combined oxygen-glucose deprivation in primary neurons in vitro as well as in caspase-associated cell death, stroke volume, and neurological impairment after cerebral ischemia in vivo. These processes were rescued by lentiviral Faim2 gene transfer. In summary, we provide evidence that Faim2 is a novel neuroprotective molecule in the context of cerebral ischemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Brain Infarction / etiology
  • Brain Infarction / prevention & control*
  • Caspase 3 / metabolism
  • Caspase 8 / metabolism
  • Cell Death / genetics
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Disease Models, Animal
  • Gene Expression Regulation / genetics
  • Glucose / deficiency
  • Green Fluorescent Proteins / genetics
  • Hypoxia
  • In Situ Nick-End Labeling / methods
  • Ischemic Attack, Transient / complications*
  • Ischemic Attack, Transient / genetics
  • Ischemic Attack, Transient / pathology*
  • Membrane Proteins / deficiency
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / genetics
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / metabolism*
  • Nervous System Diseases / etiology
  • Nervous System Diseases / prevention & control
  • Phosphopyruvate Hydratase / metabolism
  • Time Factors
  • Transfection / methods
  • fas Receptor / genetics
  • fas Receptor / metabolism*

Substances

  • Membrane Proteins
  • Nerve Tissue Proteins
  • fas Receptor
  • lifeguard protein, mouse
  • Green Fluorescent Proteins
  • Caspase 3
  • Caspase 8
  • Phosphopyruvate Hydratase
  • Glucose