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- W2891577239 endingPage "e1007283" @default.
- W2891577239 startingPage "e1007283" @default.
- W2891577239 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." @default.
- W2891577239 created "2018-09-27" @default.
- W2891577239 creator A5013847668 @default.
- W2891577239 creator A5032728621 @default.
- W2891577239 creator A5033488965 @default.
- W2891577239 creator A5033809126 @default.
- W2891577239 creator A5084855980 @default.
- W2891577239 creator A5090589412 @default.
- W2891577239 date "2018-09-20" @default.
- W2891577239 modified "2023-09-25" @default.
- W2891577239 title "Prions activate a p38 MAPK synaptotoxic signaling pathway" @default.
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