A Mutant Prion Protein Sensitizes Neurons to Glutamate-Induced Excitotoxicity

Departments of Biochemistry and Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts 02118, Dulbecco Telethon Institute and Departments of Neuroscience and Biochemistry and Molecular Pharmacology, Mario Negri Institute for Pharmacological Research, I-20156 Milan, Italy, and Institute of Neurology, Medical University of Vienna, A-1097 Vienna, Austria.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 02/2013; 33(6):2408-18. DOI: 10.1523/JNEUROSCI.3406-12.2013
Source: PubMed

ABSTRACT Growing evidence suggests that a physiological activity of the cellular prion protein (PrP(C)) plays a crucial role in several neurodegenerative disorders, including prion and Alzheimer's diseases. However, how the functional activity of PrP(C) is subverted to deliver neurotoxic signals remains uncertain. Transgenic (Tg) mice expressing PrP with a deletion of residues 105-125 in the central region (referred to as ΔCR PrP) provide important insights into this problem. Tg(ΔCR) mice exhibit neonatal lethality and massive degeneration of cerebellar granule neurons, a phenotype that is dose dependently suppressed by the presence of wild-type PrP. When expressed in cultured cells, ΔCR PrP induces large, ionic currents that can be detected by patch-clamping techniques. Here, we tested the hypothesis that abnormal ion channel activity underlies the neuronal death seen in Tg(ΔCR) mice. We find that ΔCR PrP induces abnormal ionic currents in neurons in culture and in cerebellar slices and that this activity sensitizes the neurons to glutamate-induced, calcium-mediated death. In combination with ultrastructural and biochemical analyses, these results demonstrate a role for glutamate-induced excitotoxicity in PrP-mediated neurodegeneration. A similar mechanism may operate in other neurodegenerative disorders attributable to toxic, β-rich oligomers that bind to PrP(C).

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May 19, 2014