title: Role of lipid rafts and GM1 in the segregation and processing of prion protein.
abstract: The prion protein (PrPC) is highly expressed within the nervous system. Similar to other GPI-anchored proteins, PrPC is found in lipid rafts, membrane domains enriched in cholesterol and sphingolipids. PrPC raft association, together with raft lipid composition, appears essential for the conversion of PrPC into the scrapie isoform PrPSc, and the development of prion disease. Controversial findings were reported on the nature of PrPC-containing rafts, as well as on the distribution of PrPC between rafts and non-raft membranes. We investigated PrPC/ganglioside relationships and their influence on PrPC localization in a neuronal cellular model, cerebellar granule cells. Our findings argue that in these cells at least two PrPC conformations coexist: in lipid rafts PrPC is present in the native folding (α-helical), stabilized by chemico-physical condition, while it is mainly present in other membrane compartments in a PrPSc-like conformation. We verified, by means of antibody reactivity and circular dichroism spectroscopy, that changes in lipid raft-ganglioside content alters PrPC conformation and interaction with lipid bilayers, without modifying PrPC distribution or cleavage. Our data provide new insights into the cellular mechanism of prion conversion and suggest that GM1-prion protein interaction at the cell surface could play a significant role in the mechanism predisposing to pathology.
authors.affiliation: Department of Health Science - Medical School, University of Milano-Bicocca, Monza, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Botto
authors.affiliation: Department of Health Science - Medical School, University of Milano-Bicocca, Monza, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Cunati
authors.affiliation: Department of Health Science - Medical School, University of Milano-Bicocca, Monza, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Coco
authors.affiliation: Department of Health Science - Medical School, University of Milano-Bicocca, Monza, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sesana
authors.affiliation: Department of Health Science - Medical School, University of Milano-Bicocca, Monza, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bulbarelli
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Biasini
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Colombo
authors.affiliation: Department of Biomedical Sciences, University of Padova, Padova, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Negro
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiesa
authors.affiliation: Department of Health Science - Medical School, University of Milano-Bicocca, Monza, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Masserini
authors.affiliation: Department of Health Science - Medical School, University of Milano-Bicocca, Monza, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Palestini
mesh_terms: D000818:Animals; D005677:G(M1) Ganglioside / Q000737:chemistry / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018621:PrPC Proteins / Q000737:chemistry / Q000378:metabolism; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D059748:Proteolysis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008051:Lipid Bilayers; D018621:PrPC Proteins; D018620:PrPSc Proteins; D005677:G(M1) Ganglioside