title: Discriminating between cellular and misfolded prion protein by using affinity to 9-aminoacridine compounds.
abstract: Quinacrine and related 9-aminoacridine compounds are effective in eliminating the alternatively folded prion protein, termed PrP(Sc), from scrapie-infected cultured cells. Clinical evaluations of quinacrine for the treatment of human prion diseases are progressing in the absence of a clear understanding of the molecular mechanism by which prion replication is blocked. Here, insight into the mode of action of 9-aminoacridine compounds was sought by using a chemical proteomics approach to target identification. Cellular macromolecules that bind 9-aminoacridine ligands were affinity-purified from tissue lysates by using a 9-aminoacridine-functionalized solid-phase matrix. Although the 9-aminoacridine matrix was conformationally selective for PrP(Sc), it was inefficient: approximately 5 % of PrP(Sc) was bound under conditions that did not support binding of the cellular isoform, PrP(C). Our findings suggest that 9-aminoacridine compounds may reduce the PrP(Sc) burden either by occluding epitopes necessary for templating on the surface of PrP(Sc) or by altering the stability of PrP(Sc) oligomers, where a one-to-one stoichiometry is not necessary.
authors: Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
authors: Puay-Wah
authors: PW
authors: Phuan
authors: Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
authors: Julie A
authors: JA
authors: Zorn
authors: Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA.|Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
authors: Jiri
authors: J
authors: Safar
authors: Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA.|Department of Neurology, University of California San Francisco, San Francisco, CA, USA.|Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.
authors: Kurt
authors: K
authors: Giles
authors: Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.|Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA.|Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
authors: Stanley B
authors: SB
authors: Prusiner
authors: Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
authors: Fred E
authors: FE
authors: Cohen
authors: Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA.|Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
authors: Barnaby C H
authors: BCH
authors: May
mesh_terms: D000585:Aminacrine / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D006224:Cricetinae; D008647:Mesocricetus; D051379:Mice; D008822:Mice, Transgenic; D018621:PrPC Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D018620:PrPSc Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding
chemical_list: D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; D000585:Aminacrine