Prion replication alters the distribution of synaptophysin and caveolin 1 in neuronal lipid rafts

The main event in the pathogenesis of prion diseases is the conversion of the cellular prion protein (PrPC) into the abnormal, protease-resistant prion protein (PrPres). PrPC is a GPI-anchored protein located in lipid rafts or detergent-resistant membranes (DRMs). Here we describe the association of PrP with DRMs in neuronal cell bodies and axons during the course of murine scrapie and its relation with the distribution of the PrP-interacting proteins caveolin I and synaptophysin. Scrapie infection triggered the accumulation of PrPres in DRMs from retinas and optic nerves from early stages of the disease before evidence of neuronal cell loss. Most of the PrPres remained associated with lipid rafts throughout different stages in disease progression. In contrast to PrPres, caveolin 1 and synaptophysin in retina and optic nerves shifted to non-DRM fractions during the course of scrapie infection. The accumulation of PrPres in DRMs was not associated with a general alteration in their composition, because no change in the total protein distribution across the sucrose gradient or in the flotation characteristics of the glycosphingolipid GM1 or Thy-1 were observed until advanced stages of the disease. However, an increase in total cholesterol levels was observed in optic nerve and retinas. Only during late stages of the disease was a decrease in the number of neuronal cell bodies observed, suggesting that synaptic abnormalities are the earliest sign of neuronal dysfunction that ultimately results in neuronal death. These results indicate that prion replication triggers an abnormal localization of caveolin 1 and synaptophysin, which in turn may alter neuronal function.