Dopamine induces the accumulation of insoluble prion protein and affects autophagic flux

Author(s)

da Luz, Marcio H. M. ^{[1, 2]} ; Peres, Italo T. ^[2] ; Santos, Tiago G. ^[3] ; Martins, Vilma R. ^[3] ; Icimoto, Marcelo Y. ^[4] ; Lee, Kil S. ^[2]

Affiliation

^[1] Univ Metodista Sao Paulo, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Dept Biochem Mol & Cell Biol, BR-04039032 Sao Paulo - Brazil

^[3] AC Camargo Canc Ctr, Int Res Ctr, Sao Paulo - Brazil

^[4] Univ Fed Sao Paulo, Dept Biophys, BR-04039032 Sao Paulo - Brazil

• Document type: Journal article
• Source: FRONTIERS IN CELLULAR NEUROSCIENCE; v. 9, FEB 2 2015.
• Web of Science Citations: 6

Abstract

Accumulation of protein aggregates is a histopathological hallmark of several neurodegenerative diseases, but in most cases the aggregation occurs without defined mutations or clinical histories, suggesting that certain endogenous metabolites can promote aggregation of specific proteins. One example that supports this hypothesis is dopamine and its metabolites. Dopamine metabolism generates several oxidative metabolites that induce aggregation of alpha-synuclein, and represents the main etiology of Parkinson's diseases. Because dopamine and its metabolites are unstable and can be highly reactive, we investigated whether these molecules can also affect other proteins that are prone to aggregate, such as cellular prion protein (PrPC). In this study, we showed that dopamine treatment of neuronal cells reduced the number of viable cells and increased the production of reactive oxygen species (ROS) as demonstrated in previous studies. Overall PrPC expression level was not altered by dopamine treatment, but its unglycosylated form was consistently reduced at 100 mu M of dopamine. At the same concentration, the level of phosphorylated mTOR and 4EBP1 was also reduced. Moreover, dopamine treatment decreased the solubility of PrPC, and increased its accumulation in autophagosomal compartments with concomitant induction of LC3-II and p62/SQSTM1 levels. In vitro oxidation of dopamine promoted formation of high-order oligomers of recombinant prion protein. These results suggest that dopamine metabolites alter the conformation of PrPC, which in turn is sorted to degradation pathway, causing autophagosome overload and attenuation of protein synthesis. Accumulation of PrPC aggregates is an important feature of prion diseases. Thus, this study brings new insight into the dopamine metabolism as a source of endogenous metabolites capable of altering PrPC solubility and its subcellular localization. (AU)

• FAPESP's process: 13/22413-5 - Alterations of biochemical properties and functions of PrPc induced by endogenous dopamine metabolites and oligomeric amyloid beta peptide
• Grantee: Kil Sun Lee
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/18093-2 - Formation of PrPC aggregates induced by dopamine metabolites and activation of adaptive responses to unfolded proteins
• Grantee: Márcio Henrique Mello da Luz
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 08/06152-9 - Involvement of GABAergic and adenosinergic systems in PrPC function associated to sleep and circadian rhythm
• Grantee: Kil Sun Lee
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 09/14027-2 - Mechanisms associated with the function of prion protein and its ligand STI1/Hop: therapeutic approaches
• Grantee: Vilma Regina Martins
• Support Opportunities: Research Projects - Thematic Grants