Ferrari G, Greene L A
Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Perspect Dev Neurobiol. 1996;3(2):93-100.
The purpose of this article is to present the concept that the capacity of ganglioside GM1 to promote neuronal survival, and probably other differentiative and neuroprotective actions, is dependent on activation of neurotrophic factor receptor tyrosine kinases. Exogenously supplied ganglioside GM1 mimics or potentiates many activities of neurotrophic factors, including maintenance of survival, stimulation of neurite outgrowth, and protection from excitotoxic and neurotoxic insults. The mechanism of such actions has been largely unknown. We have found that GM1 will rescue cultured sympathetic neurons and PC12 (pheochromocytoma) cells from apoptotic death induced by withdrawal of nerve growth factor (NGF) or serum and have exploited these model systems to study the ganglioside mechanism of action. We have found evidence that part of the survival-promoting activity of GM1 is dependent on the presence, dimerization, and activation of the Trk NGF receptor tyrosine kinase and that GM1 causes a detectable increase in Trk receptor autophosphorylation. We postulate that exogenously supplied GM1 causes increased ligand-independent dimerization of Trk molecules within membranes, thereby leading to its activation and promotion of survival. We further speculate that GM1 may have similar effects on other receptor tyrosine kinases and that such actions could account for its mimicry and potentiation of neurotrophic factors in vitro as well as in vivo.
本文的目的是提出这样一个概念，即神经节苷脂GM1促进神经元存活的能力，以及可能的其他分化和神经保护作用，取决于神经营养因子受体酪氨酸激酶的激活。外源性提供的神经节苷脂GM1模拟或增强神经营养因子的许多活性，包括维持存活、刺激神经突生长以及保护免受兴奋性毒性和神经毒性损伤。这种作用的机制在很大程度上尚不清楚。我们发现GM1能够挽救因撤除神经生长因子（NGF）或血清而诱导凋亡死亡的培养交感神经元和PC12（嗜铬细胞瘤）细胞，并利用这些模型系统来研究神经节苷脂的作用机制。我们发现有证据表明，GM1促进存活的部分活性取决于Trk NGF受体酪氨酸激酶的存在、二聚化和激活，并且GM1会导致Trk受体自身磷酸化的可检测增加。我们推测，外源性提供的GM1会导致膜内Trk分子的配体非依赖性二聚化增加，从而导致其激活并促进存活。我们进一步推测，GM1可能对其他受体酪氨酸激酶有类似的作用，并且这种作用可以解释其在体外以及体内对神经营养因子的模拟和增强作用。
