Laser Heike, Mack Till G A, Wagner Diana, Coleman Michael P
Institute for Genetics and ZMMK, Cologne, Germany.
J Neurosci Res. 2003 Dec 15;74(6):906-16. doi: 10.1002/jnr.10806.
Proteasome inhibitors such as lactacystin were first isolated when assaying their ability to stimulate neurite outgrowth in neuronal-like cell lines; however, their effect on neurites in primary culture has been largely neglected. We report here that lactacystin causes immediate arrest of nerve growth factor (NGF)-stimulated neurite outgrowth in sympathetic and sensory explant cultures. This is followed by neurite degeneration that in sympathetic cultures has a distinctive "dying-back" morphology. Remarkably, this occurs even at concentrations below that required to induce neurite outgrowth in PC12 cells. Thus, lactacystin opposes rather than potentiates the effect of NGF on sympathetic neurite outgrowth and the role of the ubiquitin proteasome pathway in growth and long-term maintenance of axons and dendrites differs from that in neuritogenesis in neuronal-like cell lines. Retrograde degeneration caused by blocking of the ubiquitin proteasome pathway may mimic some aspects of gracile axonal dystrophy, a dying-back axonopathy in mice caused by ubiquitin hydrolase (Uch-l1) deficiency, and may be relevant to human neurodegenerative diseases involving ubiquitination or proteasome abnormalities.
蛋白酶体抑制剂如乳胞素最初是在检测其刺激类神经细胞系中神经突生长的能力时分离得到的；然而，它们对原代培养神经突的影响在很大程度上被忽视了。我们在此报告，乳胞素会使交感神经和感觉外植体培养物中神经生长因子（NGF）刺激的神经突生长立即停止。随后是神经突退化，在交感神经培养物中具有独特的“回退”形态。值得注意的是，即使在低于诱导PC12细胞神经突生长所需的浓度下也会发生这种情况。因此，乳胞素对交感神经突生长的作用是相反的，而不是增强NGF的作用，并且泛素蛋白酶体途径在轴突和树突的生长及长期维持中的作用与在类神经细胞系神经发生中的作用不同。由泛素蛋白酶体途径阻断引起的逆行性退化可能模拟了小鼠中由泛素水解酶（Uch-l1）缺乏引起的一种回退性轴突病——薄束轴索性营养不良的某些方面，并且可能与涉及泛素化或蛋白酶体异常的人类神经退行性疾病有关。
