The accumulation of misfolded proteins is a hallmark feature of several brain and peripheral diseases known as Protein Misfolding Disorders (PMDs). Alzheimer?s disease (AD) is relevant among PMDs due to its high incidence among the elderly. Unfortunately, AD cases are expected to rise considerably in the future. At this moment, the mechanisms associated to the origin and progression of AD are not completely understood. Several risk factors have been associated to increase the risks to develop AD. Cross-seeding of misfolded proteins has been listed as one of them but has been poorly explored. In this project, we aim to study whether exposure of infectious prions may lead to the misfolding and aggregation of proteins other than the cellular prion protein. Specifically, we will explore the possibility that sub-clinical prion infection by Chronic Wasting Disease (CWD) and scrapie prions cross-seed the misfolding of A? and/or tau proteins associated to AD. We will explore this hypothesis using a battery of techniques, including protein aggregation assays, biosensor cells, and animal models of sporadic and familial AD. As inocula, several animal prion strains will be used. Results from this project may lead to novel hypotheses involving the zoonotic potential of infectious prions, as well as unveil alternative mechanisms of AD progression. Future research will address the degree of interaction between other misfolded proteins.
Until now, the zoonotic potential of prions has been studied only from the human prion protein perspective. In this project, we will assess the possible cross-seeding between infectious prions and proteins associated to Alzheimer?s disease pathogenesis (A? and tau). This research may unveil novel mechanisms in which animal prions affect humans.
| Pritzkow, Sandra; Morales, Rodrigo; Lyon, Adam et al. (2018) Efficient prion disease transmission through common environmental materials. J Biol Chem 293:3363-3373 |
| Kramm, Carlos; Pritzkow, Sandra; Lyon, Adam et al. (2017) Detection of Prions in Blood of Cervids at the Asymptomatic Stage of Chronic Wasting Disease. Sci Rep 7:17241 |
| Morales, Rodrigo (2017) Prion strains in mammals: Different conformations leading to disease. PLoS Pathog 13:e1006323 |
