Zurn A D, Winkel L, Menoud A, Djabali K, Aebischer P
Gene Therapy Center, Lausanne University Medical School, Switzerland.
J Neurosci Res. 1996 Apr 15;44(2):133-41. doi: 10.1002/(SICI)1097-4547(19960415)44:2<133::AID-JNR5>3.0.CO;2-E.
We have previously shown that glial cell line-derived neurotrophic factor (GDNF), in addition to promoting the survival of dopaminergic neurons in cultures from embryonic rat ventral mesencephalon,also increases the activity of choline acetyltransferase (ChAT) in the cranial motoneurons present in these cultures (Zurn et al.: Neuroreport 6:113-118, 1994). By using the intermediate filament protein peripherin as a motoneuron marker, we report here that GDNF increases the number of motoneurons as well as the length of their neurites. Brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) also promote ChAT activity, motoneuron survival, and neurite outgrowth in these cultures, but to varying degrees. Although these three molecules have similar effects on cultured motoneurons, we provide evidence for a distinct mode of action of GDNF, BDNF, and CNTF, since combinations of GDNF and BDNF, GDNF and CNTF, and BDNF and CNTF have either additive or synergistic effects on ChAT activity and motoneuron number. In addition to the previously described motoneuron-specific neurotrophic factors BDNF and CNTF, GDNF combined with the latter two factors may provide an important tool for the treatment of human motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy, both by increasing efficiency of treatment, and by decreasing the likelihood of deleterious side-effects.
我们先前已经表明，胶质细胞系源性神经营养因子（GDNF）除了能促进胚胎大鼠腹侧中脑培养物中多巴胺能神经元的存活外，还能增加这些培养物中颅运动神经元的胆碱乙酰转移酶（ChAT）活性（祖恩等人：《神经报告》6:113 - 118，1994年）。通过使用中间丝蛋白外周蛋白作为运动神经元标记物，我们在此报告，GDNF能增加运动神经元的数量及其神经突的长度。脑源性神经营养因子（BDNF）和睫状神经营养因子（CNTF）在这些培养物中也能促进ChAT活性、运动神经元存活和神经突生长，但程度不同。尽管这三种分子对培养的运动神经元有相似的作用，但我们提供了证据表明GDNF、BDNF和CNTF有不同的作用方式，因为GDNF与BDNF、GDNF与CNTF以及BDNF与CNTF的组合对ChAT活性和运动神经元数量有相加或协同作用。除了先前描述的运动神经元特异性神经营养因子BDNF和CNTF外，GDNF与后两种因子联合使用可能为治疗人类运动神经元疾病，如肌萎缩侧索硬化症和脊髓性肌萎缩症，提供一种重要工具，既能提高治疗效果，又能降低有害副作用的可能性。
