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

Nature volume 388, pages 769–773 (1997)Cite this article

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.

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Figure 1: Physical and genetic map of the Lurcher locus and the GluRδ2 gene on mouse chromosome 6 (refs 10,11).
Figure 2: Mutation in the GluRδ2 gene in Lc and LcJ.
Figure 3: Lc/+ Purkinje cells express a large, constitutively active and selective resting conductance.
Figure 4: A large, constitutive conductance of GluRδ2Lc expressed in Xenopus oocytes.

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Acknowledgements

We thank W. Hu for technical assistance; R. MacKinnon and J. Imredy for advice and help with oocyte physiology experiments; colleagues of the Heintz and Linden laboratories for discussion and support; and C. Desplan, R. Duvoisin, J. Friedman, A. Hirano, A. J. Hudspeth, A. S. Peterson, N. Segil and Z. P. Sun for critical reading of the manuscript. J.Z., W.J. and N.H. are supported by HHMI; P.L.D. is supported by NIH/NIGMS; D.J.L. is supported by PHS MH51106, the McKnight Foundation, the Develbiss Fund, and the National Alliance for Research on Schizophrenia and Depression.

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Authors and Affiliations

  1. Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA

    Jian Zuo, Philip L. De Jager, Weining Jiang & Nathaniel Heintz

  2. Department of Neuroscience, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, 21205, Maryland, USA

    Kanji A. Takahashi & David J. Linden

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  1. Jian Zuo
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Correspondence to Nathaniel Heintz.

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Zuo, J., De Jager, P., Takahashi, K. et al. Neurodegeneration in Lurcher mice caused by mutation in δ2 glutamate receptor gene. Nature 388, 769–773 (1997). https://doi.org/10.1038/42009

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