Scrapie-infected mice and PrP knockout mice share abnormal localization and activity of neuronal nitric oxide synthase

PrPSc, the only identified component of the scrapie prion, is a conformatio nal isoform of PrPc. The physiological role of PrPc, a glycolipid-anchored glycoprotein, is still unknown. We have shown previously that neuronal nitr ic oxide synthase (nNOS) activity is impaired in the brains of mice sick wi th experimental scrapie as well as in scrapie-infected neuroblastoma cells. In this work we investigated the cell localization of nNOS in brains of wi ld-type and scrapie-infected mice as well as in mice in which the PrP gene was ablated. We now report that whereas in wild-type mice, nNOS, like PrPc, is associated with detergent-insoluble cholesterol-rich membranous microdo mains (rafts), this is not the case in brains of scrapie-infected or in tho se of adult PrPO/O mice. Also, adult PrPO/O, like scrapie-infected mice, sh ow reduced nNOS activity. We suggest that PrPc may play a role in the targe ting of nNOS to its proper subcellular localization. The similarities of nN OS properties in PrPO/O as compared with scrapie-infected mice suggest that at least this role of PrPc may be impaired in scrapie-infected brains.