Biology of Prion Protein and the TSE Diseases

National Institute Of Allergy And Infectious Diseases

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Abstract

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. We previously documented the molecular details of the neuroinflammatory response in brain following scrapie infection. In FY17 we treated scrapie-infected mice with statin drugs to attempt to reduce neuroinflammation and prolong survival. In previous studies treatment of scrapie-infected mice with the Type 1 statins, simvastatin or pravastatin, showed a small beneficial effect on survival time. In the current study, to increase the effectiveness of statin therapy, we treated infected mice with atorvastatin, a Type 2 statin that has improved pharmacokinetics over many Type 1 stains. Treatments with either simvastatin or pravastatin were tested for comparison. We evaluated scrapie-infected mice for PrPres accumulation, gliosis, neuroinflammation, and time until advanced clinical disease requiring euthanasia. All three statin treatments reduced total serum cholesterol 40% in mice. However, gliosis and PrPres deposition were similar in statin-treated and untreated infected mice. Time to euthanasia due to advanced clinical signs was not changed in statin-treated mice relative to untreated mice, a finding at odds with previous reports. Our studies indicate that none of the three statins tested was effective in reducing scrapie-induced neuroinflammation or neuropathogenesis. In FY17 we examined the pathology and ultrastructure of disease-induced PrPSc in organs outside the brain and spinal cord in a model where anchorless PrP is deposited as amyloid aggregates in various tissues. Amyloid PrPSc fibrils identified by immunogold-labeling were visible at high magnification in interstitial regions and around blood vessels of heart, brown fat, white fat, colon, and lymphoid tissues. PrPSc amyloid was located on and outside the plasma membranes of adipocytes in brown fat and cardiomyocytes, and appeared to invaginate and disrupt the plasma membranes of these cell types, suggesting cellular damage. In contrast, no cellular damage was apparent near PrPSc associated with macrophages in lymphoid tissues and colon, with enteric neuronal ganglion cells in colon or with adipocytes in white fat. PrPSc localized in macrophage phagolysosomes lacked discernable fibrils and might be undergoing degradation. Furthermore, in contrast to wild-type mice expressing GPI-anchored PrP, in lymphoid tissues of tg anchorless mice, PrPSc was not associated with follicular dendritic cells (FDC), and FDC did not display typical prion-associated pathogenic changes. Thus, amyloid PrPSc appeared to induce specific damage to certain cell types during prion infection of mice expressing anchorless PrP.