QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lu, W. Articles by Tsirka, S. E. Search for Related Content PubMed PubMed Citation Articles by Lu, W. Articles by Tsirka, S. E. Social Bookmarking                         What's this?

Partial rescue of neural apoptosis in the Lurcher mutant mouse through elimination of tissue plasminogen activator

Program in Molecular and Cellular Pharmacology and Department of Pharmacological Sciences, University Medical Center at Stony Brook, NY 11794-8651

*Author for correspondence (e-mail: stella{at}pharm.sunysb.edu)

Accepted 24 January 2002

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 2 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.

Key words: tPA, Apoptosis, Lurcher, Cerebellum, Purkinje, Neurodegeneration, Mouse

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				W. Lu, M. Bhasin, and S. E. Tsirka Involvement of Tissue Plasminogen Activator in Onset and Effector Phases of Experimental Allergic Encephalomyelitis J. Neurosci., December 15, 2002; 22(24): 10781 - 10789. [Abstract] [Full Text] [PDF]