title: Structure-activity analysis and antiprion mechanism of isoprenoid compounds.
abstract: The prion strain-specific mechanism by which normal prion protein is converted to abnormal prion protein remains largely unknown. This study found that insect juvenile hormone III reduced abnormal prion protein levels only in cells infected with the RML prion. We conducted a structure-activity analysis using juvenile hormone III biosynthetic intermediates in the isoprenoid pathway. Both farnesol and geranylgeraniol, the most potent inhibitors of abnormal prion protein formation, behaved in an RML prion-dependent fashion. Neither of them modified cellular and cell surface prion protein levels. Events downstream of this pathway include cholesterol biosynthesis and protein prenylation. However, neither of these isoprenoid compounds modified lipid raft microdomains and cellular cholesterol levels and neither affected the representative prenylated protein expression levels of prenylation pathways. Therefore, these isoprenoid compounds are a new class of prion strain-dependent antiprion compounds. They are useful for exploring strain-specific prion biology.
authors.affiliation: Department of Neurochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryocho, Sendai 980-8575, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Hamanaka
authors.affiliation: Department of Neurochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryocho, Sendai 980-8575, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nishizawa
authors.affiliation: Department of Neurochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryocho, Sendai 980-8575, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sakasegawa
authors.affiliation: Department of Neurochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryocho, Sendai 980-8575, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Teruya
authors.affiliation: Department of Neurochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryocho, Sendai 980-8575, Japan. Electronic address: doh-ura@med.tohoku.ac.jp.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Doh-ura
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051379:Mice; D015394:Molecular Structure; D011328:Prions / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D011328:Prions; D013729:Terpenes
keywords: Antiprion; Cholesterol; Farnesol; Geranylgeraniol; Isoprenoid; Juvenile hormone; N2a cell; Prenylation; Prion; Strain