TY - JOUR
T1 - A mutant prion protein sensitizes neurons to glutamate-induced excitotoxicity
AU - Biasini, Emiliano
AU - Unterberger, Ursula
AU - Solomon, Isaac H.
AU - Massignan, Tania
AU - Senatore, Assunta
AU - Bian, Hejiao
AU - Voigtlaender, Till
AU - Bowman, Frederick P.
AU - Bonetto, Valentina
AU - Chiesa, Roberto
AU - Luebke, Jennifer
AU - Toselli, Paul
AU - Harris, David A.
PY - 2013/2/6
Y1 - 2013/2/6
N2 - 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'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 (ΔCR PrP) provide important insights into this problem. Tg(Δ 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, Δ 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(Δ CR) mice. We find that (Δ 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, β-rich oligomers that bind to PrPC.
AB - 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'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 (ΔCR PrP) provide important insights into this problem. Tg(Δ 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, Δ 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(Δ CR) mice. We find that (Δ 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, β-rich oligomers that bind to PrPC.
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U2 - 10.1523/JNEUROSCI.3406-12.2013
DO - 10.1523/JNEUROSCI.3406-12.2013
M3 - Article
C2 - 23392670
AN - SCOPUS:84873288135
VL - 33
SP - 2408
EP - 2418
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 6
ER -