Projects per year
The conversion or misfolding of the normal, cell-surface glycoprotein PrPC into a conformationally altered isoform (PrPSc) forms the basis of the prion hypothesis. As PrPSc is thought to be the infectious agent detection of this abnormal protein in the brain is a common marker of prion disease. In our experiments inoculation of transgenic mice expressing a proline to leucine mutation at PrP codon 101 (101LL) with refolded recombinant PrP indicated that PrP amyloid plaques may be seeded in the brain in the absence of prion disease or replication of prion infectivity. Subsequent subpassages produced further amyloid seeding but no prion disease. We clearly demonstrate here that abnormal forms of PrP can exist in the brain without causing a spongiform encephalopathy. PrP misfolding can also be separated from propagation of prion infectivity as PrP amyloid accumulation can be induced in 101LL transgenic mice in the absence of infected inoculum. Interestingly throughout these experiments we observed that wild type control mice were all negative for plaque deposition following inoculation. We could therefore hypothesise that in the absence of this point mutation the “healthy” brain can maintain homeostasis and efficiently clear any abnormal protein present. Further investigation of these mechanisms is crucial to fully understand amyloid interactions within a healthy brain and whether elements such as age for example would be an important factor regarding homeostasis. Future work will focus on the initial interactions, processing, trafficking, accumulation and degradation of fluorescently labeled amyloid which will be monitored both in vivo using 101LL and WT animals (young/ aged) and in vitro using primary cell culture and organotypic brain slice models. This work will help advance our understanding of the initial mechanisms of protein misfolding and or amyloid production/ clearance which is essential with regard to the worlds aging population today.
|Publication status||Published - 19 Jun 2013|
|Event||National Institutes of Bioscience Conference 2013 - The Roslin Institute, Edinburgh, United Kingdom|
Duration: 18 Jun 2013 → 20 Jun 2013
|Conference||National Institutes of Bioscience Conference 2013|
|Period||18/06/13 → 20/06/13|
FingerprintDive into the research topics of 'Mechanisms of Early Misfolded Protein Accumulation/ Clearance.'. Together they form a unique fingerprint.
- 2 Finished
1/05/08 → 28/02/11
- 1 Article
Jeffrey, M., McGovern, G., Chambers, E. V., King, D., Gonzalez, L., Manson, J. C., Ghetti, B., Piccardo, P. & Barron, R. M., 2012, In: Brain Pathology. 22, 1, p. 58-66 9 p.
Research output: Contribution to journal › Article › peer-reviewOpen AccessFile