A Mutant Prion Protein Sensitizes Neurons to Glutamate-Induced Excitotoxicity

作者：Biasini Emiliano^*; Unterberger Ursula; Solomon Isaac H; Massignan Tania; Senatore Assunta; Bian Hejiao; Voigtlaender Till; Bowman Frederick P; Bonetto Valentina; Chiesa Roberto; Luebke Jennifer; Toselli Paul; Harris David A

来源：Journal of Neuroscience, 2013, 33(6): 2408-2418.

DOI：10.1523/JNEUROSCI.3406-12.2013

Growing evidence suggests that a physiological activity of the cellular prion protein (PrPC) plays a crucial role in several neurodegenerative disorders, including prion and Alzheimer%26apos;s diseases. However, how the functional activity of PrPC 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 Delta CR PrP) provide important insights into this problem. Tg(Delta CR) 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, Delta CR 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(Delta CR) mice. We find that Delta CR 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, beta-rich oligomers that bind to PrPC.

• 出版日期2013-2-6