Abstract
Synaptic degeneration is one of the earliest pathological correlates of prion disease, and it is a major determinant of the progression of clinical symptoms. However, the cellular and molecular mechanisms underlying prion synaptotoxicity are poorly understood. Previously, we described an experimental system in which treatment of cultured hippocampal neurons with purified PrPSc, the infectious form of the prion protein, induces rapid retraction of dendritic spines, an effect that is entirely dependent on expression of endogenous PrPC by the target neurons. Here, we use this system to dissect pharmacologically the underlying cellular and molecular mechanisms. We show that PrPSc initiates a stepwise synaptotoxic signaling cascade that includes activation of NMDA receptors, calcium influx, stimulation of p38 MAPK and several downstream kinases, and collapse of the actin cytoskeleton within dendritic spines. Synaptic degeneration is restricted to excitatory synapses, spares presynaptic structures, and results in decrements in functional synaptic transmission. Pharmacological inhibition of any one of the steps in the signaling cascade, as well as expression of a dominant-negative form of p38 MAPK, block PrPSc-induced spine degeneration. Moreover, p38 MAPK inhibitors actually reverse the degenerative process after it has already begun. We also show that, while PrPC mediates the synaptotoxic effects of both PrPSc and the Alzheimer’s Aβ peptide in this system, the two species activate distinct signaling pathways. Taken together, our results provide powerful insights into the biology of prion neurotoxicity, they identify new, druggable therapeutic targets, and they allow comparison of prion synaptotoxic pathways with those involved in other neurodegenerative diseases.
Highlights
Prion diseases are a group of fatal, infectious neurodegenerative diseases affecting humans and animals
We showed that treatment of cultured hippocampal neurons for 24 hrs with purified PrPSc, but not control preparations, induced a dramatic retraction of dendritic spines, an effect that was entirely dependent on expression of endogenous PrPC by the neurons [23]
We used patch clamp recording to measure the amplitude and frequency of miniature excitatory postsynaptic currents in hippocampal neurons treated with PrPSc. mEPSCs, which are recorded in the presence of TTX to block action potentials and picrotoxin to block GABA-evoked inhibitory currents, are a measure of spontaneous synaptic currents evoked by glutamate
Summary
Prion diseases are a group of fatal, infectious neurodegenerative diseases affecting humans and animals. Prions propagate themselves by a highly specific templating process in which PrPSc molecules impose their unique, β-sheet-rich conformations on endogenous PrPC substrate molecules [1,2,3,4]. Consistent with this model, PrP knockout mice, in which PrPC expression is absent, are completely resistant to prion infection [5, 6]. It is important to understand the molecular mechanism of PrPSc neurotoxicity
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