title: Lurcher GRID2-induced death and depolarization can be dissociated in cerebellar Purkinje cells.
abstract: The Lurcher mutation transforms the GRID2 receptor into a constitutively opened channel. In Lurcher heterozygous mice, cerebellar Purkinje cells are permanently depolarized, a characteristic that has been thought to be the primary cause of their death, which occurs from the second postnatal week onward. The more dramatic phenotype of Lurcher homozygotes is thought to be due to a simple gene dosage effect of the mutant allele. We have analyzed the phenotype of Lurcher/hotfoot heteroallelic mutants bearing only one copy of the Lurcher allele and no wild-type Grid2. Our results show that the absence of wild-type GRID2 receptors in these heteroallelic mutants induces an early and massive Purkinje cell death that is correlated with early signs of autophagy. This neuronal death is independent of depolarization and can be explained by the direct activation of autophagy by Lurcher GRID2 receptors through the recently discovered signaling pathway formed by GRID2, n-PIST, and Beclin1.
authors.affiliation: Laboratoire Développement et Vieillissement du Système Nerveux, CNRS-UMR 7102, Université Pierre et Marie Curie, 75005 Paris, France.
authors.forename: Fekrije
authors.initials: F
authors.lastname: Selimi
authors.forename: Ann M
authors.initials: AM
authors.lastname: Lohof
authors.forename: Stéphane
authors.initials: S
authors.lastname: Heitz
authors.forename: Alexis
authors.initials: A
authors.lastname: Lalouette
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Jarvis
authors.forename: Yannick
authors.initials: Y
authors.lastname: Bailly
authors.forename: Jean
authors.initials: J
authors.lastname: Mariani
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology*; D017470:Receptors, Glutamate / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics
chemical_list: D017470:Receptors, Glutamate; C107913:glutamate receptor delta 2