Menu bar Introduction Main menu Timeline Pathogen cards Student pages Small but deadly Fast Facts External sources

Recent RESEARCH & PUBLICATIONS, 2007-2008

Parkyn CJ, Vermeulen EG, Mootoosamy RC, Sunyach C, Jacobsen C, Oxvig C, Moestrup S, Liu Q, Bu G, Jen A, Morris RJ.
LRP1 controls biosynthetic and endocytic trafficking of neuronal prion protein. J Cell Sci 2008 Feb 19.

Endocytosing PrP(c) is believed to be a limiting factor for changing it to the PrP(sc) isoform. Parkyn et al. showed that low-density lipoprotein receptor-related protein 1 (LRP1) binds to PrP(c) during endocytosis, which is a necessary step. PrP(c) is normally found on the neuronal surface, and lowered LRP1 levels by siRNA showed lower levels of surface PrP(c). The N-terminal domain of PrP(c), which contains amino acids that aid in endocytosis, also binds to LRP1 with incredible affinity. This article argues that LRP1 controls the surface and biosynthetic movement of PrP(c) in neurons.

Jenkins DC, Sylvester ID, Pinheiro TJ.
The elusive intermediate on the folding pathway of the prion protein. Febs J 2008 Feb 12.

As mentioned in the “Small but Deadly” section, subsection on Molecular Pathogenesis, how PrP(sc) induces PrP(c) to change conformation is not fully understood. It’s likely that a PrP intermediate form (PrP*) is involved in the conformation change, but PrP* has not yet been isolated. In order to investigate the PrP’s folding pathway, Jenkins et al. expressed two mutants, each possessing single tryptophan residue at a known location. The mutants’ secondary structure and folding properties were observed. Using conventional analyses of folding transition data determined by fluorescence and CD, and novel phase-diagram analyses, we present compelling evidence for the presence of an intermediate species on the folding pathway of PrP.

Kong Q, Zheng M, Casalone C, Qing L, Huang S, Chakraborty B, Wang P, Chen F, Cali I, Corona C, Martucci F, Iulini B, Acutis P, Wang L, Liang J, Wang M, Li X, Monaco S, Zanusso G, Zou WQ, Caramelli M, Gambetti P.
Evaluation of the Human Transmission Risk of an Atypical Bovine Spongiform Encephalopathy Prion Strain. J Virol. 2008 Jan 30.  

Before 2004, BSE-C was the only prion strain known to cause bovine spongiform encephalopathy in cattle. Two atypical strains, BASE (BSE-L) and BSE-H were discovered, but their infectivities were unknown. Kong et al. inoculated BASE into transgenic mice (Tg40), engineered to express human prion protein (PrP-129M). BASE had an incubation time of 185±12 days, and BSE-C had an incubation time of 230±7 days. This shows that BASE has a higher transmission rate than BSE-C. However, only 60% of the BASE-inoculated mice developed clinical disease, and 100% of BSE-C-infected mice did. This means a species barrier still exists between BASE and humans. Some BASE-inoculated mice had infectious prions in their spleen, which shows that BASE is likely lymphotropic.

Gerber R, Tahiri-Alaoui A, Hore PJ, James W.
Conformational pH dependence of intermediate states during oligomerization of the human prion protein. Protein Sci 2008 Mar;17(3):537-44.

PrP(c) forms a soluble beta-sheet-rich oligomer under acidic, mildly denaturing, high salt conditions. Gerber et al. observes alpha-helical secondary structures at pH 4.1 in a monomeric intermediate form of PrP. At pH 3.6, beta-sheets were found to predominate. The alpha-helical intermediate formed at pH 4.1 could convert to the beta-sheet conformation at pH 3.6, but not vice versa, and neither state can be reconverted to an alpha-monomer.

Andrievskaia O, Algire J, Balachandran A, Nielsen K.
Prion protein in sheep urine. J Vet Diagn Invest. 2008 Mar;20(2):141-6.

Soluble PrP(c) has been detected in cerebrospinal fluid, urine, serum, milk, and seminal plasma. This study sought to quantify the amount of PrP(c) in naturally scrapie-infected sheep (n=33) compared to normal sheep (n=16). Urine samples from scrapie-infected sheep and comparable healthy sheep were collected and analyzed by Western blot. Concentration of PrP(c) in normal sheep was found to be 0-0.16 ng/ml. Seven out of 33 naturally scrapie-infected animals had an elevated level (0.3-4.7 ng/ml) of PrP(c) in urine. The origin of PrP(c) in urine and the reason for the increased level of PrP(c) in scrapie-infected sheep urine is unknown as of yet.

Return to Main Menu