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The Journal of Neuroscience, July 8, 2009, 29(27):8743-8751; doi:10.1523/JNEUROSCI.2294-09.2009

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Neurobiology of Disease
Phosphorylation of Prion Protein at Serine 43 Induces Prion Protein Conformational Change

Paresa N. Giannopoulos,¹ Catherine Robertson,^2,3 Julie Jodoin,^1,4 Hemant Paudel,^1,4 Stephanie A. Booth,^2,3 and Andrea C. LeBlanc^1,4

¹The Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, The Sir Mortimer B. Davis Jewish General Hospital, Montréal, Québec H3T 1E2, Canada, ²Molecular Pathobiology, National Microbiology Laboratory, Winnipeg, Manitoba R3E 3R2, Canada, ³Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada, and ⁴Department of Neurology and Neurosurgery, McGill University, Montréal, Québec H3A 2T5, Canada

Correspondence should be addressed to Dr. Andréa LeBlanc, The Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, The Sir Mortimer B. Davis Jewish General Hospital, 3755 Chemin Côte Ste-Catherine, Montréal, QC H3T 1E2, Canada. Email: andrea.leblanc{at}mcgill.ca

The cause of the conformational change of normal cellular prion protein (PrP) into its disease-associated form is unknown. Posttranslational modifications, such as glycosylation, acetylation, S-nitrosylation, and phosphorylation, are known to induce protein conformational changes. Here, we investigated whether phosphorylation could induce the conformational change of PrP because PrP contains several kinase motifs and has been found recently in the cytosol, in which kinases generally reside. Neuronal cyclin-dependent kinase 5 (Cdk5) phosphorylated recombinant PrP_23–231 at serine 43 (S43) in an in vitro kinase assay. Cdk5-phosphorylated PrP became proteinase K resistant, formed Congo Red-positive fibrils, and formed aggregates that were immunostained with anti-PrP and anti-phospho-PrP^S43 (anti-pPrP^S43). pPrP^S43 was detected in PrP/Cdk5/p25 cotransfected N2a cells. Roscovitine inhibition of Cdk5 activity or transfection of N2a cells with mutant PrP S43A eliminated the anti-pPrP^S43-immunopositive protein. Alkaline phosphatase-sensitive and proteinase K-resistant pPrP^S43 immunoreactivity was observed in scrapie-infected but not control-injected mice brains. These results raise the possibility that phosphorylation could represent a physiological mechanism of PrP conversion in vivo.

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Received May 15, 2009; accepted June 3, 2009.

Correspondence should be addressed to Dr. Andréa LeBlanc, The Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, The Sir Mortimer B. Davis Jewish General Hospital, 3755 Chemin Côte Ste-Catherine, Montréal, QC H3T 1E2, Canada. Email: andrea.leblanc{at}mcgill.ca

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