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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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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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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DOI: https://doi.org/10.1038/42009
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