Group leader: Prof. Judit Ovadi
One of our objectives is to understand the molecular mechanism of the development of neurodegenerative processes initiated by unfolded/misfolded proteins, and to affect the aberrant protein-protein interactions leading to formation of inclusions in brain.
Recently we have isolated and identified a new brain-specific protein termed TPPP/p25 (Tubulin Polymerization Promoting Protein) the major target of which is the microtubule system. TPPP/p25 affects the dynamics and stability of microtubule network under physiological conditions. Under pathological conditions it is enriched within inclusions of pathological human brain tissues characteristics for Parkinson but not Alzheimer diseases. We work on the characterization of the structural, functional and pathological features of TPPP/p25, identify its homologous proteins for comparative studies, and search for additional targets.
Triosephosphate isomerase deficiency is an unique glycolytic enzymopathy coupled with neurodegeneration. We have characterized the structure, the association properties of the mutant isomerase, and evaluated the consequences of mutation at metabolic level. Recently we reported that the mutation itself cannot be responsible for the development of neurodegenerative sympthoms and for the early death of patients. We are searching factors that play predominant role in the development of the neurodegeneration in order to propose powerful tool for monitoring and treatment of this disease.
Another objective is to evaluate the mechanism of actions of bisindol anti-cancer agents, and to design derivatives without toxic side effects. We have identified a new antimitotic pharmacofor, KAR-2, determined the 3D structure of this drug complexed with its target protein, calmodulin, and evaluated of the mechanism of its action. These data suggested that the anti-calmodulin activity of the bisindols using in chemotherapy could be responsible for the undesired toxic side effects. Our aim is to identify the calmodulin-modulated process(es) the impairment of which is responsible for the toxic side effect of the mother molecule, vinblastine.
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TPPP/p25: a new microtubule-targeting protein
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The initiative for our research in this field was the discovery of a new tubulin-targeting protein. We noticed that an extract from brain, but not from muscle, contains a protein that promotes formation of tubulin assemblies. The purified protein from bovine brain was identified as the basic, heat resistant, about 25 kDa protein that had been found in a partially purified fraction of bovine tau protein kinase II. The bovine and human proteins (termed p25) were cloned, and found to exhibit 90% structural identity.
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Molecular bases of triosephosphate isomerase deficiency
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Triosephosphate isomerase (TPI) also binds to tubulin/microtubules and the binding is enforced by the mutations causing disease. TPI deficiency is the only one among glycolytic enzymopathies in which hemolytic anemia is coupled with neurodegeneration. In a Hungarian family with severe decrease in triosephosphate isomerase (TPI) activity, two germ-line identical, but phenotypically differing compound heterozygote brothers inherited two independent (Phe240Leu and Glu145stop codon) mutations.
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KAR-2: novel anti-cancer drugs with distinct pharmacology
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Cancer continues to be one of the major health and socio-economic problems despite considerable progress in its early diagnosis and treatment. The search for new anti-cancer drugs and the development of more effective treatment strategies is a field of utmost importance in current drug discovery and clinical research. Anti-cancer drug discovery has focused extensively on targets related to mitosis, a crucial phase of cell cycle progression, the miscontrol and uncontrol of which can lead to development of human tumours. The major constituent of the highly dynamic mitotic spindle is the microtubule. Thus, the MT system is the primary target of important clinical anti-cancer drugs such as vinca alkaloids or taxol or their derivatives.
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