Involvement of the ubiquitin-proteasome system in the early stages of Wallerian degeneration

被引:268
作者
Zhai, QW
Wang, J
Kim, A
Liu, Q
Watts, R
Hoopfer, E
Mitchison, T
Luo, LQ
He, ZG
机构
[1] Childrens Hosp, Div Neurosci, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA
[3] Stanford Univ, Dept Biol Sci, Stanford, CA 94305 USA
关键词
D O I
10.1016/S0896-6273(03)00429-X
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Local axon degeneration is a common pathological feature of many neurodegenerative diseases and peripheral neuropathies. While it is believed to operate with an apoptosis-independent molecular program, the underlying molecular mechanisms are largely unknown. In this study, we used the degeneration of transected axons, termed "Wallerian degeneration," as a model to examine the possible involvement of the ubiquitin proteasome system (UPS). Inhibiting UPS activity by both pharmacological and genetic means profoundly delays axon degeneration both in vitro and in vivo. In addition, we found that the fragmentation of microtubules is the earliest detectable change in axons undergoing Wallerian degeneration, which among other degenerative events, can be delayed by proteasome inhibitors. Interestingly, similar to transected axons, degeneration of axons from nerve growth factor (NGF)-deprived sympathetic neurons could also be suppressed by proteasome inhibitors. Our findings suggest a possibility that inhibiting UPS activity may serve to retard axon degeneration in pathological conditions.
引用
收藏
页码:217 / 225
页数:9
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