Conformational changes of proteins in mental disorders
Conformational Changes of Proteins in Mental Disorders: Detection, Development of Assay Methods And Searching for Ways of Correction
Tech Area / Field
- BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology
- MED-DID/Diagnostics & Devices/Medicine
- PHY-OPL/Optics and Lasers/Physics
8 Project completed
Senior Project Manager
VNIIEF, Russia, N. Novgorod reg., Sarov
- Institute of Psychiatry, Russia, Moscow\nInstitute of Physical Chemical Medicine, Russia, Moscow
- University of Maryland / School of Medicine / Department of Biochemistry and Molecular Biology, USA, MD, Baltimore\nErnst-Moritz-Arndt-Universität Greifswald / Institut für Pathologie, Germany, Greifswald\nUniversitat Leipzig / Institut fuer Medizinische Physik und Biophysik, Germany, Leipzig\nNational University of Ireland, Ireland, Galway
Project summaryA significant rise of social and medical consequences of mental disorders: schizophrenia, depression, unpredictable behavior etc. - takes place recent years. Number of people who need control and correction of their mental state increases reaching 6-15 per cent of the total population. Probably, in 10-15 years mental disorders would be the first cause of temporal incapacity for work exceeding cardio-vascular diseases and cancer. Such mental disorders as unmotivated aggression and unpredictable behavior involved children and became a burning social problem in many countries, including Russia.
Progress in creating new effective methods of diagnostics, therapy and preventing mental disorders is limited by insufficient understanding of molecular mechanisms that play important role in development of both mental and somatic components of these diseases.
Recently it has been shown that conformational changes of molecules of some proteins (so-called prions) can be an important unit of the chain of molecular processes that lead to mental disorders. But prion-dependent mental disorders are an exotic case. At the same time our recently obtained data have shown that conformational changes of serum albumin, the main transport protein of human blood plasma, accompany mental disorders in the majority patients. This very important protein carries fatty acids, one of the major sources of energy, to brain. Albumin participates in oxidative processes, joins many other metabolic processes that play an important role in pathogenesis of mental disorders. These transport, oxidative and other functions of albumin molecule are conformation-dependent.
The major aim of the project is to clarify details of molecular changes in albumin molecule at mental disorders. Clarification of these details would be a basis for new laboratory methods for the evaluation of the efficacy of therapy and the prognosis of these disorders. Moreover, this knowledge could be a probable basis for creating new methods for the correction of these disorders by correction of conformational changes of albumin molecules as well as the understanding of the pathogenetic mechanisms of mental disorders.
The first step of this study will be a reliable registration of these disease-related conformational changes of albumin molecule and estimation of value of these changes. For this purpose several physical methods will be used. The first one is time-resolved fluorescence spectroscopy with picosecond time resolution. This method allows to register small local changes of the main binding sites of albumin. Secondly, we will try to use small-angle neutron scattering to estimate changes of total size and shape of albumin molecule at these mental disorders. Third method is nuclear magnetic resonance in its different versions: this method is sensitive to local state of different albumin chemical groups as well as global changes of albumin and its hydration shell.
Our preliminary data, using time-resolved fluorescence spectroscopy, have shown that this method allows to detect difference in molecular dynamics of albumin molecules between healthy donors and psychotic patients; this difference becomes apparent at time resolution of tens picoseconds. To study these processed in human blood in detail, a new special picosecond laser device will be made with time resolution of 50 picoseconds to measure absorption and fluorescence in blood of healthy persons and mental disorders patients.
All patients under investigation will be tested by standard biochemical and other laboratory methods including testes for hormonal status, parameters of endogenous intoxication, neurochemical status etc to compare them with the newly obtained data.
A special attention will be given to patients with initial stages of these disorders before therapy because any therapy could influence the blood parameters.
Results of the Project would be a theoretical basis for 1) creating a new laboratory method for the control of patient’s state and 2) the development of the goal-directed approaches for the correction of the conformational changes of albumin molecules in patients with mental disorders.
Basic Participants of the Project and their qualification:
(1) Head institution RFNC-VNIIEF: development and manufacturing the unique laser facility for performing investigations of albumin conformation.
The Institute has a large experience in laser techniques including oscillation and compression of laser pulses, laser radiation – matter interaction, quantum physics, stimulated Raman scattering, etc. and creating optical registration systems with high time resolution (up to 20 picosec). There is a technical base and facilities for time-resolved experiments.
(2) MRIP PHM RF: One of the major Russian medical centers in the field of clinical psychiatry.
(3) RIPCM PHM RF: This is a leading center in Russia in the field of using fluorescent methods for studying molecular structures and functions in medico-biological research and creation new fluorescent methods for clinical diagnostics.