Biology of Prion Protein and the TSE Diseases

点击翻译按钮获取中文摘要

Prion diseases or transmissible spongiform encephalopathies are infectious neurodegenerative diseases of humans and animals. A major feature of prion diseases is the refolding and aggregation of a normal host protein, prion protein (PrP), into a disease-associated protease-resistant form (PrPres) which may contribute to brain damage. In FY13 we studied the formation of the amyloid and non-amyloid forms of disease-associated protease-resistant prion protein (PrPres) in scrapie-infected mice. After scrapie infection in transgenic mice expressing anchorless PrP, amyloid is deposited in brain mainly in the perivascular pattern similar to cerebral amyloid angiopathy (CAA) seen in Alzheimers disease and some genetic brain diseases in humans. In our experiments, PrPres amyloid co-localized with microinjected FITC-ovalbumin, a marker of the brain interstitial fluid (ISF) drainage system, suggesting that distribution of precursors of amyloid PrPres by ISF flow might be a part of the pathogenesis leading to CAA. These studies also demonstrated that PrPres was associated with three types of vessels including capillaries, arteries and veins. In contrast to the results seen in transgenic mice, infection of mice expressing anchored PrP gave rise to non-amyloid PrPres which was not associated with blood vessels or with ISF tracers. In FY13 we also studied the effect of PrP expression on sensitivity to kainate-induced seizures in mice. Previous studies by other groups suggested that PrP knockout mice were more sensitive to such seizures. However, our experiments using studying PrP deletion using three different mouse genetic backgrounds showed that PrP deletion sometimes made mice less sensitive to kainate-induced seizures. Furthermore, using genetic complementation studies in vivo, we found that non-PrP genes in the region flanking the deleted PrP gene appeared to be responsible for the effects which appeared to correlate with PrP deletion.