A Neuronal Culture System to Detect Prion Synaptotoxicity

Abstract

<div><p>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 PrP<sup>Sc</sup>, 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, PrP<sup>C</sup>, by target neurons, and on the presence of a nine-amino acid, polybasic region at the N-terminus of the PrP<sup>C</sup> molecule. Both protease-resistant and protease-sensitive forms of PrP<sup>Sc</sup> 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 PrP<sup>Sc</sup> and testing potential therapeutic agents.</p></div

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