11810634

pubmed:Citation

3

The mechanisms of injury-induced apoptosis of neurons within the spinal cord are not understood. We used a model of peripheral nerve-spinal cord injury in the rat and mouse to induce motor neuron degeneration. In this animal model, unilateral avulsion of the sciatic nerve causes apoptosis of motor neurons. We tested the hypothesis that p53 and Bax regulate this neuronal apoptosis, and that DNA damage is an early upstream signal. Adult mice and rats received unilateral avulsions causing lumbar motor neurons to achieve endstage apoptosis at 7-14 days postlesion. This motor neuron apoptosis is blocked in bax(-/-) and p53(-/-) mice. Single-cell gel electrophoresis (comet assay), immunocytochemistry, and quantitative immunogold electron microscopy were used to measure molecular changes in motor neurons during the progression of apoptosis. Injured motor neurons accumulate single-strand breaks in DNA by 5 days. p53 accumulates in nuclei of motor neurons destined to undergo apoptosis. p53 is functionally activated by 4-5 days postlesion, as revealed by immunodetection of phosphorylated p53. Preapoptotically, Bax translocates to mitochondria, cytochrome c accumulates in the cytoplasm, and caspase-3 is activated. These results demonstrate that motor neuron apoptosis in the adult spinal cord is controlled by upstream mechanisms involving DNA damage and activation of p53 and downstream mechanisms involving upregulated Bax and cytochrome c and their translocation, accumulation of mitochondria, and activation of caspase-3. We conclude that adult motor neuron death after nerve avulsion is DNA damage-induced, p53- and Bax-dependent apoptosis.

eng

IM

MEDLINE

0022-3034

Copyright 2002 John Wiley & Sons, Inc.

15

NLM

181-97

pubmed-meshheading:11810634-Animals, pubmed-meshheading:11810634-Apoptosis, pubmed-meshheading:11810634-Caspase 3, pubmed-meshheading:11810634-Caspases, pubmed-meshheading:11810634-Cell Count, pubmed-meshheading:11810634-Cytochrome c Group, pubmed-meshheading:11810634-DNA, pubmed-meshheading:11810634-DNA Damage, pubmed-meshheading:11810634-Immunohistochemistry, pubmed-meshheading:11810634-Male, pubmed-meshheading:11810634-Mice, pubmed-meshheading:11810634-Mice, Inbred C57BL, pubmed-meshheading:11810634-Mitochondria, pubmed-meshheading:11810634-Motor Neurons, pubmed-meshheading:11810634-Proto-Oncogene Proteins, pubmed-meshheading:11810634-Proto-Oncogene Proteins c-bcl-2, pubmed-meshheading:11810634-Rats, pubmed-meshheading:11810634-Rats, Sprague-Dawley, pubmed-meshheading:11810634-Sciatic Nerve, pubmed-meshheading:11810634-Spinal Cord Injuries, pubmed-meshheading:11810634-Tumor Suppressor Protein p53, pubmed-meshheading:11810634-bcl-2-Associated X Protein

Injury-induced spinal motor neuron apoptosis is preceded by DNA single-strand breaks and is p53- and Bax-dependent.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S.