title: Neurodegeneration in Lurcher mice occurs via multiple cell death pathways.
abstract: Lurcher (Lc) is a gain-of-function mutation in the delta2 glutamate receptor (GRID2) that results in the cell-autonomous death of cerebellar Purkinje cells in heterozygous lurcher (+/Lc) mice. This in turn triggers the massive loss of afferent granule cells during the first few postnatal weeks. Evidence suggests that the death of Purkinje cells as a direct consequence of GRID2(Lc) activation and the secondary death of granule cells because of target deprivation occur by apoptosis. We have used mice carrying null mutations of both the Bax and p53 genes to examine the roles of these genes in cell loss in lurcher animals. The absence of Bax delayed Purkinje cell death in response to the GRID2(Lc) mutation and permanently rescued the secondary death of granule cells. In contrast, the p53 deletion had no effect on either cell death pathway. Our results demonstrate that target deprivation induces a Bax-dependent, p53-independent cell death response in cerebellar granule cells in vivo. In contrast, Bax plays a minor role in GRID2(Lc)-mediated Purkinje cell death.
authors.affiliation: Laboratory of Molecular Biology and Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10021, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Doughty
authors.forename: P L
authors.initials: PL
authors.lastname: De Jager
authors.forename: S J
authors.initials: SJ
authors.lastname: Korsmeyer
authors.forename: N
authors.initials: N
authors.lastname: Heintz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants / Q000235:genetics*; D009410:Nerve Degeneration / Q000473:pathology*; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein
chemical_list: C494827:Bax protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases