Predicting Prion Propensity of Human Proteins

Abstract

In humans only a single prion-forming protein named PrP^c (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. Taking advantage of the compositional similarity of these proteins to the known yeast prions, I plan to use the prion prediction methodology that our lab has pioneered to develop an entirely new algorithm specifically suited for this class of neuronal proteins.