Injury-induced apoptosis of neurons in adult brain is mediated by p53-dependent and p53-independent pathways and requires Bax

Lee J. Martin, Adeel Kaiser, Jonathan W. Yu, Joanne E. Natale, Nael A. Al-Abdulla

Research output: Contribution to journalArticle

Abstract

The mechanisms of injury-induced apoptosis of neurons within the CNS are not understood. We used a model of cortical injury in rat and mouse to induce retrograde neuronal apoptosis in thalamus. In this animal model, unilateral ablation of the occipital cortex causes unequivocal apoptosis of corticopetal projection neurons in the dorsal lateral geniculate nucleus (LGN) by 7 days postlesion. We tested the hypothesis that p53 and Bax regulate this retrograde neuronal apoptosis. We found, by using immunocytochemistry, that p53 accumulates in nuclei of neurons destined to undergo apoptosis. By immunoblotting, p53 levels increase (∼150% of control) in nuclear-enriched fractions of the ipsilateral LGN by 5 days after occipital cortex ablation, p53 is functionally activated in nuclear fractions of the ipsilateral LGN at 5 days postlesion, as shown by DNA binding assay (∼fourfold increase) and by immunodetection of phosphorylated p53. The levels of procaspase-3 increase at 4 days postlesion, and caspase-3 is activated prominently at 5 days postlesion. To identify whether neuronal apoptosis in the adult brain is dependent on p53 and Bax, cortical ablations were done on p53 and bax null mice. Neuronal apoptosis in the dorsal LGN is significantly attenuated (∼34%) in p53-/- mice. In lesioned p53+/+ mice, Bax immunostaining is enhanced in the ipsilateral dorsal LGN and Bax immunoreactivity accumulates at perinuclear locations in dorsal LGN neurons. The enhancement and redistribution of Bax immunostaining is attenuated in lesioned p53-/- mice. Neuronal apoptosis in the dorsal LGN is blocked completely in bax-/- mice. We conclude that neuronal apoptosis in the adult thalamus after cortical injury requires Bax and is modulated by p53.

Original languageEnglish (US)
Pages (from-to)299-311
Number of pages13
JournalJournal of Comparative Neurology
Volume433
Issue number3
DOIs
StatePublished - May 7 2001

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Keywords

  • Alzheimer's disease
  • Amyotrophic lateral sclerosis
  • DNA damage
  • Head trauma
  • Programmed cell death
  • Tumor suppressor protein

ASJC Scopus subject areas

  • Neuroscience(all)

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