Neurodegeneration in Lurcher mice caused by mutation in δ2 glutamate receptor gene

Jian Zuo, Philip L. De Jager, Kanji A. Takahashi, Weining Jiang, David J. Linden, Nathaniel Heintz

Research output: Contribution to journalArticle

Abstract

Lurcher (Lc) is a spontaneous, semidominant mouse neurological mutation. Heterozygous Lurcher mice (Lc/+)display ataxia as a result of a selective, cell-autonomous and apoptotic death of cerebellar Purkinje cells during postnatal development. Homozygous Lurcher mice (Lc/Lc) die shortly after birth because of a massive loss of mid- and hindbrain neurons during late embryogenesis. We have used positional cloning to identify the mutations responsible for neurodegeneration in two independent Lc alleles as G-to-A transitions that change a highly, conserved alanine to a threonine residue in transmembrane domain III of the mouse δ2 glutamate receptor gene (GluRδ2). Lc/+ Purkinje cells have a very high membrane conductance and a depolarized resting potential, indicating the presence of a large, constitutive inward current. Expression of the mutant GluRδ2(Lc) protein in Xenopus oocytes confirmed these results, demonstrating that Lc is inherited as a neurodegenerative disorder resulting from a gain-of-function mutation in a glutamate receptor gene. Thus the activation of apoptotic neuronal death in Lurcher mice may provide a physiologically relevant model for excitotoxic cell death.

Original languageEnglish (US)
Pages (from-to)769-773
Number of pages5
JournalNature
Volume388
Issue number6644
DOIs
StatePublished - Sep 17 1997

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    Zuo, J., De Jager, P. L., Takahashi, K. A., Jiang, W., Linden, D. J., & Heintz, N. (1997). Neurodegeneration in Lurcher mice caused by mutation in δ2 glutamate receptor gene. Nature, 388(6644), 769-773. https://doi.org/10.1038/42009