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

Abstract

PrP(Sc), the only identified component of the scrapie prion, is a conformational isoform of PrP(c). The physiological role of PrP(c), a glycolipid-anchored glycoprotein, is still unknown. We have shown previously that neuronal nitric oxide synthase (nNOS) activity is impaired in the brains of mice sick with experimental scrapie as well as in scrapie-infected neuroblastoma cells. In this work we investigated the cell localization of nNOS in brains of wild-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 PrP(c), is associated with detergent-insoluble cholesterol-rich membranous microdomains (rafts), this is not the case in brains of scrapie- infected or in those of adult PrP(o/o) mice. Also, adult PrP(o/o), like scrapie-infected mice, show reduced nNOS activity. We suggest that PrP(c) may play a role in the targeting of nNOS to its proper subcellular localization. The similarities of nNOS properties in PrP(o/o) as compared with scrapie- infected mice suggest that at least this role of PrP(c) may be impaired in scrapie-infected brains.