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Oxidative stress, nitric oxide, and the mechanisms of cell death in Lurcher Purkinje cells
Author(s) -
McFarland Rebecca,
Blokhin Andrei,
Sydnor James,
Mariani Jean,
Vogel Michael W.
Publication year - 2007
Publication title -
developmental neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.716
H-Index - 129
eISSN - 1932-846X
pISSN - 1932-8451
DOI - 10.1002/dneu.20391
Subject(s) - purkinje cell , oxidative stress , programmed cell death , biology , microbiology and biotechnology , peroxynitrite , nitric oxide , nitric oxide synthase , cerebellum , nitrotyrosine , glutamate receptor , neuroscience , receptor , apoptosis , biochemistry , endocrinology , superoxide , enzyme
Abstract Oxidative stress is postulated to play a role in cell death in many neurodegenerative diseases. As a model of neonatal neuronal cell death, we have examined the role of oxidative stress in Purkinje cell death in the heterozygous Lurcher mutant (+/ Lc ). Lurcher is a gain of function mutation in the δ2 glutamate receptor (GluRδ2) that turns the receptor into a leaky membrane channel, resulting in chronic depolarization of +/ Lc Purkinje cells starting around the first week of postnatal development. Virtually, all +/ Lc Purkinje cells die by the end of the first postnatal month. To investigate the role of oxidative stress in +/ Lc Purkinje cell death, we have examined nitric oxide synthase (NOS) activity and the expression of two markers for oxidative stress, nitrotyrosine and manganese super oxide dismutase (MnSOD), in wild type and +/ Lc Purkinje cells at P10, P15, and P25. The results show that NOS activity and immunolabeling for nitrotyrosine and MnSOD are increased in +/ Lc Purkinje cells. To determine whether peroxynitrite formation is a prerequisite for +/ Lc Purkinje cell death, +/ Lc mutants were crossed with an α‐nNOS knockout mutant (nNOSα −/− ) to reduce the production of NO. Analysis of the double mutants showed that blocking α‐nNOS expression does not rescue +/ Lc Purkinje cells. However, we present evidence for sustained NOS activity and nitrotyrosine formation in the GluRδ2 +/ Lc :nNOS −/− double mutant Purkinje cells, which suggests that the failure to rescue GluRδ2 +/ Lc :nNOS −/− Purkinje cells may be explained by the induction of alternative nNOS isoforms. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007.