Manganese-induced Parkinson's Disease: the role of YPK9 protein

Several metals have toxic actions on nerve cells, playing a role in the genesis and development of many neurodegenerative diseases. In particular, manganese is a well known neurotoxic metal as it accumulates in basal ganglia inducing Manganism, a disorder with common symptoms with Parkinson's disease. It was recently found that YPK9 protein, Yeast PARK9, also known as YOR291W, can protect cells from manganese poisoning. In fact, YPK9 is a non essential yeast gene predicted by sequence to encode a transmembrane P5-type transport ATPase which is apparently involved in metal coordination and transportation. Mutations in its human orthologue, ATP13A2/PARK9, have been linked to genetic forms of juvenile Parkinsonism. We tested the binding ability of Mn(II) and others divalent cations (Ca(II), Cu(II), Zn(II) and Ni(II)) with two peptide sequences from YPK9 with a particular focus on the highly conserved sequences from yeast to human. The work was carried out at different pH values and ligand to metal molar ratios by using several spectroscopic techniques such as multidimensional and heteronuclear NMR as well as EPR, in order to evaluate and compare the coordination propensities of the fragments towards Mn(II) and the other selected metal ions. The YPK9 protective properties in Manganese-induced Parkinsonism and its role as a metal transporter protein was evaluated.