Formation of PrPC aggregates induced by dopamine metabolites and activation of adaptive responses to unfolded proteins

Abstract

Cellular prion protein (PrPC) plays several important roles in cell survival and maintenance. However, when its conformation is altered for any reason, it becomes more prone to form protein aggregates, which is a common hallmark of various neurodegenerative diseases. Given that most cases of neurodegenerative diseases are sporadic, investigation of causes that lead to protein aggregation is an essential step to developing therapeutic strategies. Oxidative metabolites have been pointed out as an important factor that causes protein aggregation. For instance, reactive oxygen species (ROS) can be produced by dopamine auto-oxidation and induce modifications in proteins. Indeed, the a-synuclein aggregation induced by dopamine metabolites is closely related to the development of Parkinson's Disease. PrPC is highly expressed in neurons and its N-terminal domain has a flexible structure with several amino acids that are more susceptible to oxidation. These factors may facilitate the preferential oxidation of PrPC by ROS, which can be a possible mechanism for the anti-oxidant role of PrPC. However, this mechanism can produce undesirable by-products, that is protein aggregates and activate unfolding protein responses (UPR). Thus, this project aims to investigate how the altered metabolism of dopamine induced by methamphetamine affects the aggregation states of PrPC and subsequent activation of the UPR. The data generated in this project can help establish a common mechanism of pathogenesis of neurodegenerative diseases, cell responses to these alterations, and a new method of treating these diseases.(AU)