title: A Neuronal Culture System to Detect Prion Synaptotoxicity.
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.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Cheng
authors.initials: C
authors.lastname: Fang
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Imberdis
authors.affiliation: Department of Biochemistry and Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Maria Carmen
authors.initials: MC
authors.lastname: Garza
authors.affiliation: Department of Biochemistry and Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Holger
authors.initials: H
authors.lastname: Wille
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Harris
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018929:Cell Culture Techniques / Q000379:methods*; D049229:Dendritic Spines / Q000473:pathology*; D004195:Disease Models, Animal; D006624:Hippocampus; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology; D018620:PrPSc Proteins / Q000633:toxicity*; D017096:Prion Diseases / Q000473:pathology; D013569:Synapses / Q000473:pathology
chemical_list: D018620:PrPSc Proteins