Prevention of neuronal apoptotic death by neurotrophic agents and ganglioside GM1: insights and speculations regarding a common mechanism.
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.
Ferrari
G
G
Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Greene
L A
LA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D005677:G(M1) Ganglioside / Q000494:pharmacology*; D006801:Humans; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D017475:Receptors, Nerve Growth Factor / Q000502:physiology
D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D017475:Receptors, Nerve Growth Factor; D005677:G(M1) Ganglioside; D020794:Receptor Protein-Tyrosine Kinases