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Neurodegeneration in Lurcher mice caused by mutation in δ2 glutamate receptor gene
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 delta2 glutamate receptor gene (GluR delta2). 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 GluR delta2(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.
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“Heterozygous Lurcher mice lose 100% of their cerebellar Purkinje cells due to a gain-of-function mutation in the δ2 glutamate receptor gene [283],”
From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [283]
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Metadata
- Authors
- Zuo, J., De Jager, P. L., Takahashi, K. A., Jiang, W., Linden, D. J., & Heintz, N.
- Affiliations
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- Corresponding author
- Heintz, Nathaniel
- Venue
- Nature
- Published
- 1997-08-21
- Volume
- 388
- Issue
- 6644
- Pages
- 769-773
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1523646668
- Cited by
- 554
- References
- 22
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 6 · 2023: 12 · 2022: 9 · 2021: 17 · 2020: 18 · 2019: 8 · 2018: 9 · 2017: 9 · 2016: 14 · 2015: 15 · 2014: 20 · 2013: 17 · 2012: 23
- FWCI
- 12.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- American-Scandinavian Foundation
- McKnight Foundation
- National Fish and Wildlife Foundation
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health
- Comisión de Investigaciones Científicas
- National Institute of Mental Health (MH 51106)
- National Institute of General Medical Sciences
- National Marine Fisheries Service
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- neurodegeneration, Purkinje cell death, apoptosis, gain-of-function mutations, excitotoxic cell death, cerebellum, ataxia, positional cloning
- MeSH terms
- Amino Acid Sequence, Animals, Chromosome Mapping, Electrophysiology, Exons, Introns, Mice, Inbred Strains, Mice, Neurologic Mutants, Molecular Sequence Data, Nerve Degeneration, Nervous System Diseases, Purkinje Cells, Recombinant Proteins, Xenopus laevis, Point Mutation, Sequence Homology, Amino Acid, Receptors, Glutamate, Polymorphism, Single-Stranded Conformational, Mice, In Vitro Techniques
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