GluR delta 2 and the development and death of cerebellar Purkinje neurons in lurcher mice.
Lurcher (Lc) is a spontaneous, semidominant mouse neurological mutation. Heterozygous lurcher mice (Lc/+) display ataxia due to a selective, cell-autonomous, apoptotic death of 90% of cerebellar Purkinje cells during postnatal development. Homozygous lurcher mice (Lc/Lc) die shortly after birth due to massive loss of mid- and hindbrain neurons during late embryogenesis. We identified the mutations responsible for neurodegeneration in two independent Lc alleles as identical G-to-A transitions that change a highly conserved alanine to a threonine residue in transmembrane domain III of the mouse delta 2 glutamate receptor gene (GluRE2). Lc/+ Purkinje cells displayed a very high membrane conductance and a depolarized resting potential, indicating the presence of a large, constitutive inward current. Expression of the mutant GluR delta 2Lc protein in Xenopus oocytes confirmed these results, demonstrating that lurcher is an inherited neurodegenerative disorder resulting from a gain-of-function mutation in a glutamate receptor gene. Further characterization of GluR delta 2 signaling and the activation of apoptotic death in Lc Purkinje cells have begun to yield mechanistic insights into this neurodegenerative disease, and to highlight its relationship to neuronal loss following ischemia.
Laboratory of Molecular Biology, Howard Hughes Medical Institute, Rockefeller University, New York, New York 10021, USA. heintz@rockvax.rockefeller.edu
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D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002525:Cerebellar Cortex / Q000378:metabolism*; D004195:Disease Models, Animal; D019143:Evolution, Molecular; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008818:Mice, Neurologic Mutants; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000235:genetics; D009865:Oocytes / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000235:genetics*; D018092:Kainic Acid Receptors / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000235:genetics; D014981:Xenopus; D000097806:GluK2 Kainate Receptor
D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor; C107913:glutamate receptor delta 2