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

• Grant number: 12/18093-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2012
• End date: October 31, 2014
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Kil Sun Lee
• Grantee: Márcio Henrique Mello da Luz
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DA LUZ, MARCIO H. M.; PERES, ITALO T.; SANTOS, TIAGO G.; MARTINS, VILMA R.; ICIMOTO, MARCELO Y.; LEE, KIL S.. Dopamine induces the accumulation of insoluble prion protein and affects autophagic flux. FRONTIERS IN CELLULAR NEUROSCIENCE, v. 9, FEB 2 2015. (13/22413-5, 12/18093-2, 08/06152-9, 09/14027-2)