Decreased levels of proteasome activity and proteasome expression in aging spinal cord

被引:226
作者
Keller, JN
Huang, FF
Markesbery, WR [1 ]
机构
[1] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA
[2] Univ Kentucky, Dept Neurol, Lexington, KY 40536 USA
[3] Univ Kentucky, Dept Pathol, Lexington, KY 40536 USA
关键词
aging; 4-hydroxynonenal; motor neuron; oxidative stress; proteasome; spinal cord;
D O I
10.1016/S0306-4522(00)00067-1
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Neuron death and neuron degeneration occur in the CNS during the course of aging. Although multiple cellular alterations transpire during the aging process, those that mediate age-associated neuron death have not been identified. Recent evidence implicates oxidative stress as a possible means of neuron death and neuron degeneration during aging. In the present study, we demonstrate a marked decrease in multicatalytic proteasome activity in the spinal cord of Fisher 344 rats at 12, 24 and 28 months, compared with spinal cord tissue from 3-week- and 3-month-old animals. Application of oxidative injury (FeSO4) or the lipid peroxidation product 4-hydroxynonenal decreases multicatalytic proteasome activity in a time- and dose-dependent manner in a motor neuron cell line. Loss of multicatalytic proteasome activity occurs before the loss of multicatalytic proteasome immunoreactivity, with FeSO4- and 4-hydroxynonenal-mediated decreases ameliorated by the application of a cell permeable form of the antioxidant glutathione. Application of multicatalytic proteasome inhibitors, but not inhibitors of lysosomal proteases, induced neuron death that was attenuated by the caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-(O-methyl) fluoromethyl ketone or N-acetyl-Asp-Glu-Val-AsD-Cho (aldehyde). Together, these data suggest that multicatalytic proteasome inhibition occurs during aging of the spinal cord, possibly as the result of oxidative stress, and that multicatalytic proteasome inhibition may be causally related to neuron death. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:149 / 156
页数:8
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