Intrinsic Resistance of Oligodendrocytes to Prion Infection

Abstract

Within the CNS, the normal form of cellular prion protein (PrP^C) is expressed on neurons, oligodendrocytes, and astrocytes. The contribution of these cell types to prion replication and pathogenesis is unclear. To assess the role of oligodendrocytes, we expressed PrP^Cunder the control of the myelin basic protein (MBP) promoter in mice lacking endogenous PrP^C. PrP^Cwas detected in oligodendrocytes and Schwann cells but not in neurons and astrocytes. MBP-PrP mice never developed scrapie after intracerebral, intraperitoneal, or intraocular challenge with scrapie prions. Transgenic brains did not contain protease-resistant prion protein and did not transmit scrapie when inoculated into PrP^C-overexpressing indicator mice. To investigate whether prion spread within the CNS depends on oligodendrocytic PrP^C, we implanted PrP^C-overexpressing neuroectodermal grafts into MBP-PrP brains. After intraocular prion inoculation, none of the grafts showed spongiform encephalopathy or prion infectivity. Hence oligodendrocytes do not support cell-autonomous prion replication, establishment of subclinical disease, and neural spread of prions. Prion resistance sets oligodendrocytes aside from both neurons and astrocytes.