NR AWDB
AU Caughey,B.W.
TI Structure, trafficking and inhibition of infectious scrapie particles
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Oral sessions ORAL-10
PT Konferenz-Vortrag
AB The wide diversity of known or postulated PrP-res particle sizes and ultrastructures raises questions as to which are the most infectious and smallest infectious units. Size-based fractionations of partially fragmented 263K PrP-res aggregates in detergent showed that non-fibrillar particles, with masses equivalent to 14-28 PrP molecules, are by far the most infectious particles per unit protein, while particles smaller than PrP hexamers had no converting activity. As long as particles were above the minimum size, the infectivity levels appeared to be approximately proportional to particle concentration rather than PrP-res concentration. The proteinase K-resistance of PrP-res increased with particle size. To visualize the interaction between exogenous PrP-res and neuronal cells, fluorescently labeled, infectious PrP-res was used to infect cultured neurons. PrP-res aggregates were internalized into intracellular vesicles and transported along neurites to points of contact with other cells, apparently by a relatively non-specific pinocytosis or transcytosis mechanism. These experiments have visualized and characterized initial steps associated with scrapie infection and PrPres transport within neuronal cells. To find treatments for TSE diseases, we have continued to seek new inhibitors of PrP-res formation. A variety of TSE-infected cell cultures have been employed to screen for such inhibitors, including a newly developed chronic wasting disease-infected mule deer CWD. Among the recently identified inhibitors are the phosphorothioate oligonucleotides cell line, MDB (PS-ONs), which had been shown previously to have prophylactic anti-scrapie activity in the form of CpG PS-ONs. Although it had been hypothesized that the CpG PS-ONs act by stimulating innate immune mechanisms, we have found non-CpG PS-ONs can directly bind to PrPc, potently inhibit PrP-res accumulation in TSE-infected cells, and triple the survival times of scrapie-infected mice.
AD NIAID/NIH Rocky Mountain Laboratories, Hamilton, MT, USA. E-mail: bcaughey@nih.gov
SP englisch
PO Italien