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 and Nathaniel Heintz ()
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Jian Zuo: Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University
Philip L. De Jager: Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University
Kanji A. Takahashi: The Johns Hopkins University School of Medicine
Weining Jiang: Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University
David J. Linden: The Johns Hopkins University School of Medicine
Nathaniel Heintz: Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University

Nature, 1997, vol. 388, issue 6644, 769-773

Abstract: Abstract Lurcher (Lc) is a spontaneous, semidominant mouse neurological mutation1. Heterozygous Lurcher mice (Lc/+) display ataxia as a result of a selective, cell-autonomous and apoptotic death of cerebellar Purkinje cells during postnatal development2,3,4. Homozygous Lurcher mice (Lc/Lc) die shortly after birth because of a massive loss of mid- and hindbrain neurons during late embryogenesis5. 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 GluRδ2Lc 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.

Date: 1997
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DOI: 10.1038/42009

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