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Journal of Virology, April 2001, p. 3453-3461, Vol. 75, No. 7
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.7.3453-3461.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Branched Polyamines Cure Prion-Infected Neuroblastoma Cells

Surachai Supattapone,1,2 Holger Wille,1,2 Lisa Uyechi,3 Jiri Safar,1,2 Patrick Tremblay,1,2 Francis C. Szoka,3 Fred E. Cohen,1,4,5,6 Stanley B. Prusiner,1,2,6,* and Michael R. Scott1,2

Institute for Neurodegenerative Diseases,1 and Departments of Neurology,2 Biopharmaceutical Sciences,3 Cellular and Molecular Pharmacology,4 Medicine,5 and Biochemistry and Biophysics,6 University of California at San Francisco, San Francisco, California 94143

Received 30 October 2000/Accepted 14 December 2000

Branched polyamines, including polyamidoamine and polypropyleneimine (PPI) dendrimers, are able to purge PrPSc, the disease-causing isoform of the prion protein, from scrapie-infected neuroblastoma (ScN2a) cells in culture (S. Supattapone, H.-O. B. Nguyen, F. E. Cohen, S. B. Prusiner, and M. R. Scott, Proc. Natl. Acad. Sci. USA 96:14529-14534, 1999). We now demonstrate that exposure of ScN2a cells to 3 µg of PPI generation 4.0/ml for 4 weeks not only reduced PrPSc to a level undetectable by Western blot but also eradicated prion infectivity as determined by a bioassay in mice. Exposure of purified RML prions to branched polyamines in vitro disaggregated the prion rods, reduced the beta -sheet content of PrP 27-30, and rendered PrP 27-30 susceptible to proteolysis. The susceptibility of PrPSc to proteolytic digestion induced by branched polyamines in vitro was strain dependent. Notably, PrPSc from bovine spongiform encephalopathy-infected brain was susceptible to PPI-mediated denaturation in vitro, whereas PrPSc from natural sheep scrapie-infected brain was resistant. Fluorescein-labeled PPI accumulated specifically in lysosomes, suggesting that branched polyamines act within this acidic compartment to mediate PrPSc clearance. Branched polyamines are the first class of compounds shown to cure prion infection in living cells and may prove useful as therapeutic, disinfecting, and strain-typing reagents for prion diseases.

* Corresponding author. Mailing address: Institute for Neurodegenerative Diseases, Box 0518, University of California, San Francisco, CA 94143-0518. Phone: (415) 476-4482. Fax: (415) 476-8386. E-mail: hang{at}itsa.ucsf.edu.

Journal of Virology, April 2001, p. 3453-3461, Vol. 75, No. 7
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.7.3453-3461.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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