Online ISSN: 2515-8260

Author : E., Ross


Predicting Prion Propensity of Human Proteins

Cascarina S; Ross E.

European Journal of Molecular & Clinical Medicine, 2015, Volume 2, Issue 4, Pages -

In humans only a single prion-forming protein named PrPc (for “cellular prion protein”) is currently known, yet many more neurodegenerative disorders involve aberrant protein aggregation. The classical model for these diseases has involved cell-autonomous aggregation, assuming that aggregation occurs independently in each cell within a diseased patient. However, more recent models have proposed a non-cell-autonomous progression of disease in which aggregates formed in one cell may be transmitted to neighboring cells. These aggregate seeds then cause aggregation of the soluble protein in the “infected” cells, similar to the prion diseases. Within the past few years, a number of proteins that exhibit prion-like aggregation and spread to neighboring tissues have been discovered in patients with Amyotrophic Lateral Sclerosis (ALS). Although ALS has been studied for a number of decades, these proteins were only recently linked to ALS by chance. This demonstrates a clear need for an accurate method to systematically identify additional proteins that may play a pathological role in neurodegenerative disorders.

Predicting New Prion Candidates in Yeast

Shattuck J; Waetcher A; Ross E.

European Journal of Molecular & Clinical Medicine, 2015, Volume 2, Issue 4, Pages -

Prions are infectious proteins capable of self-propagating and transmitting between organisms. Even though there is no homolog to the mammalian prion protein in yeast, several soluble proteins can form heritable aggregates de novo. These proteins provide a model system to investigate the nucleation, aggregation and propagation steps involved in the formation of a prion fibril. Several prion prediction algorithms have been developed to predict yeast proteins that have the propensity to form prions. One of these algorithms was previously developed in our laboratory (Prion Aggregation Prediction Algorithm, PAPA, Toombs et al., 2012). Therefore, we used PAPA to scan the yeast proteome to extract proteins that contain domains predicted to have prion activity (prion-like domains). These prion-like domains will be tested in four prion activity assays to assess their activity in vivo as well as in vitro. Here we provide preliminary evidence that we are successful at predicting yeast proteins that present prion activity in vivo. Following characterization of these prion-like domains, we will test the respective full-length proteins for prion activity using microscopy as well as developing phenotypic assays.