Partial rescue of neural apoptosis in the Lurcher mutant mouse through elimination of tissue plasminogen activator.
Lurcher is a spontaneous mouse mutant characterized by premature and aberrant apoptosis in the cerebellum. The phenotype has been shown to be caused by a point mutation in the delta2 glutamate receptor subunit gene that results in a large constitutive inward current, which has proved that endogenous excitotoxicity can lead to apoptotic cell death. Additional studies have suggested a direct link between this endogenous excitotoxicity and the activation of intracellular cell death enzymes. We have previously shown that excitotoxic neuronal degeneration elicited through exogenous insults (e.g. excitotoxins, stroke) is promoted by an extracellular cascade involving the serine protease tissue plasminogen activator (tPA). However, whether it is through necrotic or apoptotic mechanisms that this excitotoxic cell death occurs has remained contested. We describe the attenuation of the Lurcher cell death progression in tPA-deficient mice. Elimination of tPA delayed the apoptotic death of Purkinje and granule neurons in Lurcher mice, and reduced the phosphorylation of Jun and the activation of caspase 8. These results indicate that not only does tPA-promoted excitotoxic cell death proceed through a receptor-mediated apoptotic pathway, but that neuronal cell death in the Lurcher mouse is facilitated by extracellular cascades in addition to the already described intracellular pathways. Finally, these findings suggest that therapeutic benefits may be achieved for a wide variety of insults to the CNS by regulating tPA activity to preserve neuronal viability.
Lu
Weiquan
W
Program in Molecular and Cellular Pharmacology and Department of Pharmacological Sciences, University Medical Center at Stony Brook, NY 11794-8651, USA.
Tsirka
Stella E
SE
D000818:Animals; D017209:Apoptosis; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D008818:Mice, Neurologic Mutants; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D010766:Phosphorylation; D011689:Purkinje Cells / Q000166:cytology*; D017470:Receptors, Glutamate / Q000235:genetics / Q000502:physiology*; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D017470:Receptors, Glutamate; C107913:glutamate receptor delta 2; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D010959:Tissue Plasminogen Activator; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases