Discriminating between cellular and misfolded prion protein by using affinity to 9-aminoacridine compounds.
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.
Phuan
Puay-Wah
PW
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
Zorn
Julie A
JA
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
Safar
Jiri
J
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.
Giles
Kurt
K
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.
Prusiner
Stanley B
SB
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.
Cohen
Fred E
FE
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
May
Barnaby C H
BCH
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.
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
D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; D000585:Aminacrine