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Forget about depression

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My idea of doing science research work dates back to April 2015. My school supervisor arranged a meeting with Janez Mavri, PhD, an established Slovenian researcher who is collaborating with Arieh Warshel – the 2013 Nobel Prize Winner for Chemistry. Mrs. Mozer was very doubtful of the success of such a demanding collaboration between a high school student and an expert in the complex field of molecular modeling. I had difficulties in understanding the experienced researchers the first couple of months as they use expert terms and acronyms all the time, but the more I listened, the more I understood.
Neurodegenerative and neuropsychiatric diseases represent major burden for our aging society. The total estimated worldwide cost of dementia has already reached 762 billion euros and will become a trillion euro disease by 2018 (World Alzheimer Report 2015). Understanding these processes on the molecular level is essential to develop diagnostic tools and therapy. Biochemical experimental work on macromolecules in central neural system (enzymes, transporters, receptors) is extremely demanding. Molecular modeling represents a complementary technique that gives a detailed atomic insight into the function of these macromolecules, and it is far less expensive.
Levels of biogenic amines (e. g. dopamine, serotonin and noradrenaline) are of prime importance for neurology and neuropsychiatry. As a byproduct of their decomposition, hydrogen peroxide is formed. Hydrogen peroxide is responsible for formation of reactive oxygen species and oxidative stress, which has a direct consequence to neurodegenerative diseases (e.g. Alzheimer's and Parkinson's).
Phenylethylamine (PEA) is endogenous amphetamine; it rises the levels of dopamine by blocking the dopamine active transporter and vesicular transporter. PEA is mainly metabolized by monoamine oxidase B, the activity of which critically depends on point mutations. By using multiscale molecular modeling simulation, we calculated the change of reactivity for Tyr326Ile point mutation of monoamine oxidase B catalyzed decomposition of PEA.
Mutant enzyme is less reactive than the wild type and the activation free energy is by 1.06 kcal/mol higher. This is in reasonable agreement with the experimental value of 0.78 kcal/mol. Mutant enzyme is 6.0 times less active than the wild type, thus giving a significant rise to PEA levels. Consenquently, the levels of dopamine in the synapse are higher. The results are discussed in terms of precision medicine applied to neuropsychiatry and have to be experimentally tested in a biochemical laboratory.
With very similar approaches, one can predict what effects point mutations in the monoamine transporters will have. With the understanding what are the effects of polymorphism of serotonin transporters and MAO A on the serotonin level, one can suggest optimal treatment of major depression disorder that critically depends on the serotonin level. The choice whether treatment will consist from inhibition of MAO A or the serotonin transporter (SERT) is a nice example of precision medicine in the field of psychiatry.
Finally, yet importantly, understanding of MAO enzymes and monoamine transporters is a prerequisite for development of novel drugs. Drugs to treat behavioral disorders are needed more than any time in the history. There are estimates that 10 % of the population of Slovenia is consuming SERT inhibitors. Precision medicine could possibly create a rebirth of the field of psychiatry.

Supervisors: Urška Jug, Jernej Stare, Janez Mavri, Alenka Mozer
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