Thesis supervisor: Katalin Várnagy
Location of studies (in Hungarian): University of Debrecen, Department of Inorganic and Analytical Chemistry Abbreviation of location of studies: D-406
Description of the research topic:
Various forms of neurodegenerative disorders represent one of the major risk for the health and future of human society. Many recent studies suggest that in addition to amyloid-β, tau protein may also play a significant role in the development of Alzheimer’s disease and/or other neurodegenerative disorders. Those neurodegenerative diseases including dementias and locomotor disorders related to tau protein known as taupathies. The common feature of neurodegenerative taupathies is, however, that tau is abnormally hyper-phosphorylated, and the hyper-phosphorylated tau aggregates into fibrils, which are accumulated in neurons and glia cells. The mechanism that leads to accumulation is still poorly understood, but it is strongly suggested that the aggregation is induced by hyper-phosporylation of the tau proteins and this processes could be affected by metal dyshomeostasis. The extent of aggregation of the protein is affected by the concentration and also by the oxidation state of the metal ions and the role of the copper or iron catalyzed redox reactions has also been reported. These previous studies strongly support the involvement of metal ions in the formation of neurofibrillary tangles but the exact characterization of the metal binding sites has not been satisfactorily clarified.
The planned work during the PhD studies:
1) The equilibrium and structural characterization of the copper(II) and zinc(II) complexes of different tau fragment containing histidine to determine
(i) how is the metal ion – peptide fragments interaction affected by different amino acid sequence around histidine;
(ii) what preference order can be given for the different metal binding sites.
2) Synthesis of some phosphorylated tau fragments and studies their copper(II) and zinc(II) complexes to clarify:
(i) how the phosphorylation of peptide affects its metal binding ability, and the structure and stability of its complexes;
(ii) whether the presence and binding of metal ion to the peptide is able to change the state of phosphorylated peptides.
The synthesis and purification of peptides will be performed by using solid phase peptide synthesizer (Liberty, CEM).
The classical pH-potentiometry will be in the center of the complexation studies for the determination of the stability constants of peptide complexes. Both the evaluation of potentiometric data and the structural determination of complexes require the application of various spectroscopic techniques, including UV-Vis, circular dichroism, 1H NMR and ESI-MS.
The redox parameters will be determined by means of cyclic voltammetry.
Required language skills: English Number of students who can be accepted: 1
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