Manganism: The Role of YPK9 Protein

Several metal ions have toxic effects on nervous cells and play a role in the genesis and development of many neurodegenerative diseases. In particular, manganese(II) ion is a well known neurotoxic metal as it accumulates in basal ganglia inducing Manganism, a pathology with common manifestations with Parkinson's disease [1]. YPK9 gene (Yeast PARK9; also known as YOR291W) encoded a protein which can protect cells from manganese poisoning [2]. In fact, YPK9 is a non-essential yeast gene predicted by sequence to encode a transmembrane P-type transport ATPase involved in metal coordination and transportation. Mutations in the human homolog of YPK9, ATP13A2/PARK9, have been linked to genetic forms of early onset Parkinsonism. We tested the binding ability of Mn(II) and other divalent metal ions (Cu(II), Zn(II), Ni(II)) with several 10 or 30 aminoacid peptide sequences from YPK9 with particular focus on highly conserved sequences from yeast to human. The work was carried out at different pH values and ligand to metal molar ratios by using potentiometric and spectroscopic techniques (multidimensional and heteronuclear NMR and UV-visible), in order to evaluate and compare the coordination ability of such fragments with Mn(II) ions and the other metal probes selected, with the purpose of sheding a light on the protective properties of YPK9 in Manganese-induced Parkinsonism [3, 4].