FORPRION

BAVARIAN RESEARCH ASSOCIATION PRIONS

Wü 1 Pathogenesis of Prion Diseases II

The spread of prions in mouse scrapie involves cells of the peripheral nervous system and cells of the immune system. It is not yet known, whether immune cells are capable to transport the infectious agent to peripheral nerve endings or if peripheral nerves are directly able to acquire prions involved in the prion pathogenesis. We investigated three mouse mutants deficient in various myelin components that not only display a de/dysmyelinating phenotype, but additionally showed elevated levels of pathogenic immune cells in their peripheral nerves. The selected mutants comprised mice homo- or heterozygously deficient in the peripheral myelin component P0 and homozygously deficient for connexin 32 (Cx32), a gap junction protein related to myelinating Schwann cells. We tested the hypothesis whether these mice show a higher susceptibility to scrapie after intraperitoneal or intranerval prion inoculation due to their higher number of immune cells in the diseased peripheral nerves. As a first step, we investigated the susceptibility of the myelin mutants and wild-type control mice after intracerebral inoculation. Mice of all genotypes were challenged either with a high or a low dose of mouse prions. As expected, the survival time strongly depended on the concentration of the pathogen, but host genotypes did not influence the survival time. As a next step, we investigated the influence of myelin deficiency and the accompanied upregulation of immune cells on the susceptibility for scrapie applying an intraperitoneal or an intranerval infection Intraperitoneally treated mice again received either a high or a low dose of prions. As expected, mice receiving the higher dose of infectious than mice which received the lower dose. There was no significant difference with regard of the survival times among the different genotypes that received a certain dose of prions. Next, peripheral nerves were directly inoculated with a high dose of prions. None of the P0-mutants (P0-/-; P0+/-) displayed altered survival times when compared with wild type controls; survival times were comparable to those of peritoneally inoculated mice. Interestingly, there was a small trend of shortened longevity of intranervally inoculated Cx32-/- mice when compared to the corresponding wild type control mice, suggesting the possibility of a minor effect of immune cells of the peripheral nerve on mouse prion pathogenesis.