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Journal of Virology, August 2005, p. 10796-10806, Vol. 79, No. 16
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.16.10796-10806.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Search for a Prion-Specific Nucleic Acid

Jiri G. Safar,1,# Klaus Kellings,2,# Ana Serban,1 Darlene Groth,1 James E. Cleaver,4 Stanley B. Prusiner,1,3,5 and Detlev Riesner2*

Institute for Neurodegenerative Diseases,1 Departments of Neurology,3 Dermatology Pharmaceutical Chemistry,4 Biochemistry and Biophysics, University of California, San Francisco, California 94143-0518,5 lnstitut für Physikalische Biologie und Biologisch-Medizinisches Forschungszentrum, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany2

Received 8 February 2005/ Accepted 12 April 2005

Diversity of prion strains was attributed to an elusive nucleic acid, yet a search spanning nearly two decades has failed to identify a prion-specific polynucleotide. In our search for a prion-specific nucleic acid, we analyzed nucleic acids in purified fractions from the brains of Syrian hamsters infected with Sc237 prions. Purification of Sc237 prions removed nucleic acids larger than 50 nucleotides as measured by return refocusing electrophoresis (RRGE). To determine the size of the largest polynucleotide present in purified fractions at an abundance of one molecule per infectious (ID50) unit, we measured prions present after inoculation. In order to account for the rapid clearance of prions after intracerebral inoculation, we determined the number of PrPSc molecules and ID50 units of prions that were retained in brain. Factoring in clearance after inoculation, we estimate that the largest polynucleotide present in our purified fractions at one molecule per ID50 unit is {approx}25 nucleotides in length. In the same fractions, there were {approx}3,000 protease-resistant PrPSc molecules per ID50 unit after accounting for clearance of PrPSc following inoculation. We compared the resistance of Sc237 and 139H prions to inactivation by UV irradiation at 254 nm. Irradiation of homogenates and microsomes diminished prion infectivity by a factor of {approx}1,000 but did not alter the strain-specified properties of the Sc237 and 139H prions. The data reported here combined with the production of synthetic prions argue that the 25-mer polynucleotides found in purified prion preparations are likely to be host encoded and of variable sequence; additionally, these 25-mers are unlikely to be prion specific.

* Corresponding author. Institut für Physikalische Biologie, Universitätsstr. 1, 40225 Düsseldorf, Germany. Phone: 49 211 81-14840. Fax: 49 211 81-15167. E-mail: riesner{at}biophys.uni-duesseldorf.de.

# These authors contributed equally.

Journal of Virology, August 2005, p. 10796-10806, Vol. 79, No. 16
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.16.10796-10806.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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