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A protein called neuropsin is essential for stress-induced neuroplastic changes – the remodeling of nerve connections in the brain – and may be a target for treating stress-related diseases.
A team of scientists led by Dr. Robert Pawlak from the University of Leicester in England has just published a groundbreaking work that describes an unknown neurochemical mechanism in the brain that triggers anxiety caused by stress and traumatic experiences. The discovery was made together with the group of Prof. Ryszard Przewłocki from the Department of Molecular Neuropharmacology of the Institute of Pharmacology of the Polish Academy of Sciences in Krakow and with the participation of Prof. Sadao Shiosaka of the Institute of Science and Technology in Naara, Japan.
Work Fri Neuropsin cleaves EphB2 in the amygdala to control anxiety ”has just been published in the most prestigious international scientific journal – Nature. The leading participation of Poles draws attention in it – the co-authors are Dr. Mariusz Mucha and Dr. Anna Skrzypiec from the British team of Dr. Pawlaka and Dr. Michał Korostyński and PhD student Marcin Piechota from the Krakow group of Prof. Przewłocki.
A brain protein that paves the way for stress
The brain’s emotional center, the amygdala (amygdala), reacts to stress by producing an enzyme called neuropsin, which activates neuronal membrane proteins. As a consequence, the activity of the amygdala increases and an anxiety response is triggered.
Since its discovery, neuropsin has been the subject of intense research. There are many publications in the scientific literature suggesting its participation in the processes of learning and memory. Until now, little was known about the biochemical mechanism by which neuropsin works in the processing of emotions. A work just published in the latest issue of the journal Nature explains this point.
Drug coding mechanism
The authors of the article described in detail and precisely proved the molecular mechanism of action of neuropsin responsible for the neuronal memory encoding of traumatic experiences.
A Polish-English-Japanese team has shown that the neuropsin released in the amygdala under stress cuts another membrane protein – the EphB2 ephrin receptor – which increases the dynamics of interaction with the NMDA receptor and, consequently, stimulates it. These processes result in the activation of the Fkbp5 gene and plastic changes in neurons. It is necessary for the perpetuation of the memory trace of the traumatic experience and can lead to the development of stress-relieving diseases – depression or post-traumatic stress disorder (PTSD). Consistent with this hypothesis, researchers showed that removing neuropsin – or its molecular partners – from nerve cells blocked the neuronal mechanism of anxiety.
“We examined the effect of a stress-induced cascade of molecular changes in the amygdala on the behavior of mice,” said Dr. Pawlak. “Stress causes animals to react to avoid danger – rodents then perceive lit, open spaces as dangerous and try to avoid them. Genetic removal of neuropsin or pharmacological inhibition of its action reduced the behavioral consequences of stress – mice were no longer afraid of dangerous places. ‘
A new way of therapy?
Dr. Pawlak adds: “Research on the new mechanism of drug formation, resulting from the intensive cooperation of specialists from various fields of neurobiology, took us the last three years. We are fascinated by this discovery. We know that all elements of the neuropsin pathway in rodents can also be found in the human brain. They may play a similar role in humans, but more research is needed to assess potential therapies for stress-induced behavior. ‘
As Professor Przewłocki explains, the action of neuropsin is necessary for the activation of the Fkbp5 gene in neurons of the amygdala nucleus, which is the main modulator of cell sensitivity to stress hormones and its polymorphisms are associated with depression and PTSD.
“The results of this study suggest that neuropsin may be the target of a new anti-stress therapy” – continues Professor Przewlocki. “The work offers hope for the development of such treatments and may contribute to the prevention of stress-induced neuropsychiatric disorders.”
Professor Przewlocki adds. “A large proportion of the population suffers from stress-induced diseases. They have a huge impact on the lives of individuals, the functioning of society and the economy. It is known that there are individual differences in susceptibility to stress, which is increasingly becoming the cause of many psychiatric illnesses. While most of us experience traumatic experiences, only a few develop stress-related illnesses such as depression, PTSD, and anxiety disorders such as phobias, panic syndromes, and generalized anxiety disorders. ” Functioning of the neuropsin pathway may, at least in part, account for these differences and the incidence of stress-induced disease.
Dr. Pawlak and Professor Przewłocki agree that although preclinical and clinical tests are needed to transfer their findings to humans, these studies open up new possibilities in this regard.
“We are conducting joint, more extensive work on the search for mechanisms and pharmacological treatment of stress-relieving diseases,” added the researchers. “We are looking for new stress-related proteins, but also for new pharmacological possibilities to restore normal brain function.”
Authors’ biographical notes
Dr. Robert Pawlak is a graduate of the Medical University of Bialystok, a neurobiologist and lecturer at the University of Leicester in Great Britain. He studies the neurobiological foundations of learning memory, anxiety and addictions. He conducted scientific research at the Department of Pharmacodynamics of his alma mater and then as a scholarship holder of the Japanese Government at the University of Hamamatsu and at the Rockefeller University in New York. He is the author of many publications in leading scientific journals, including “Nature Neuroscience”, four in “PNAS”, “Biological Psychiatry” and “Journal of Neuroscience”.
Prof. Ryszard Przewłocki is a neurobiologist and pharmacologist. He is the co-author of many fundamental papers widely cited in renowned scientific journals including Science, PNAS, Journal of Neuroscience, “GenomeBiology” and “Neuropsychopharmacology” and “Pain” and “Stroke”. His interests include the mechanisms of action of endogenous opioids, stress, pain and drug addiction, and his current interests include the molecular and genetic mechanisms of psychotropic drugs. He is the head of the Department of Molecular Neuropharmacology at the Institute of Physics PAS and the Department of Neurobiology and Neuropsychology at the Institute of Applied Psychology of the Jagiellonian University in Krakow. He is a correspondent member of the PAU.
Dr Mariusz Mucha is a molecular biologist, a graduate of the Nicolaus Copernicus University in Toruń. His area of interest is the genetic basis of neuronal activity and behavior regulation. He was a scholarship holder at the Jacques Monod Institute in Paris and then conducted research at the University of Leeds and Leicester. He is the co-author of numerous works in the field of genetics and neurobiology.
Dr Anna Skrzypiec graduated from the Faculty of Analytics at the Medical University of Bialystok. In 2008, she defended her doctoral dissertation on the neurobiological mechanisms of addiction. She has conducted research at Rockefeller University in New York, and is currently a Marie Curie Fellow of the European Commission at the University of Leicester. He is a co-author of a number of works in renowned journals in the field of neurobiology.
Dr. Michał Korostyński is a graduate of the Faculty of Biology and Environmental Protection at the University of Silesia in Katowice. In 2008, he defended his doctoral dissertation and works as an assistant professor at the Department of Molecular Neuropharmacology at the Institute of Pharmacology of the Polish Academy of Sciences in Krakow. He is a co-author of papers published in respected scientific journals such as GenomeBiology, Stroke and Pain ”. He conducts research on the molecular basis of nervous system diseases and the pharmacogenomics of psychotropic drugs.
Marcin Piechota, M.Sc., is a graduate of the Inter-Faculty Mathematics and Natural Sciences at the Jagiellonian University and Applied Psychology of the Jagiellonian University, and since 2007 a PhD student at the Department of Molecular Neuropharmacology at the Institute of Pharmacology of the Polish Academy of Sciences. His scientific achievements include 9 papers published in international journals. In 2008, he received a scholarship from the Lesser Poland scholarship fund for PhD students – Doctus. In 2011, he was awarded the START scholarship program of the Foundation for Polish Science. He is currently researching the mechanisms of regulation of changes in gene expression in the brain.