Abstract
Synaptic pathology is an early feature of prion as well as other neurodegenerative diseases. Although the self-templating process by which prions propagate is well established, the mechanisms by which prions cause synaptotoxicity are poorly understood, due largely to the absence of experimentally tractable cell culture models. Here, we report that exposure of cultured hippocampal neurons to PrPSc, the infectious isoform of the prion protein, results in rapid retraction of dendritic spines. This effect is entirely dependent on expression of the cellular prion protein, PrPC, by target neurons, and on the presence of a nine-amino acid, polybasic region at the N-terminus of the PrPC molecule. Both protease-resistant and protease-sensitive forms of PrPSc cause dendritic loss. This system provides new insights into the mechanisms responsible for prion neurotoxicity, and it provides a platform for characterizing different pathogenic forms of PrPSc and testing potential therapeutic agents.
Highlights
Prion diseases are fatal neurodegenerative conditions of humans and animals that have significantly impacted public health and the safety of the food and blood supplies
We describe a new system that is capable of reproducing acute prion neurotoxicity, based on PrPSc-induced degeneration of dendritic spines on cultured hippocampal neurons
We monitored the effect of PrPSc-containing brain homogenates on the integrity of dendritic spines displayed by differentiated cultures of hippocampal neurons
Summary
Prion diseases are fatal neurodegenerative conditions of humans and animals that have significantly impacted public health and the safety of the food and blood supplies These disorders are caused by infectious proteins called prions, which propagate themselves by a self-templating mechanism in which PrPSc, the infectious isoform, seeds conformational conversion of PrPC, a normal neuronal glycoprotein, into additional molecules of PrPSc [1,2,3]. Two-photon imaging studies of living, prion-infected animals demonstrate that swelling of dendritic shafts and retraction of dendritic spines occur early during the disease course, well before symptoms appear[12]. Taken together, these studies pinpoint synapses, in particular dendrites and dendritic spines, as important initial targets of prion neurotoxicity. Changes in their morphology are believed to underlay synaptic plasticity associated with learning and memory, as well as degenerative events that occur during aging and neurological disease[14,15]
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