Targeting TAAR5 may provide a new treatment opportunity for neurodegenerative disorders

Reviewed by Emily Henderson, B.Sc.November 11, 2020

St Petersburg University researchers, led by Professor Raul R. Gainetdinov, director of the Translational Biomedicine Institute and Academic Supervisor of St Petersburg University Hospital, have found a new role for the recently discovered neurotransmitter system that uses the trace amine associated receptor 5 (TAAR5) for neurotransmission. It has been observed that the lack of TAAR5 in mice leads to a greater number of dopaminergic neurons and an increase in adult neurogenesis, i.e. the process by which new neurons are formed in the brain. This could provide a new treatment opportunity for neurodegenerative disorders such as Parkinson’s disease.

Today, many drugs used clinically affect neurotransmission, that is, the process of communicating between neurons or transmitting signals to other cells via chemicals. Among the well-studied neurotransmitters – chemical messengers that transmit signals through the body’s nerve endings – are dopamine, norepinephrine, serotonin, histamine, and glutamate to name but a few. Earlier this year, the same group of researchers reported the discovery of a new neurotransmitter system that transmits signals from nerve cells to target cells via the trace amine-associated receptor 5 (TAAR5).

Trace Amine Associated Receptors (TAARs) are a class of receptors that detect biogenic amines, which are the products of amino acid decarboxylation. In other words, each amino acid has its own amine. As a rule, the acid part is removed by enzymes (decarboxylases) which catalyze decarboxylation. They are found in our body or in some bacteria that metabolize amino acids, for example when bacteria break down tissues. No wonder, traces of amines are abundant in fermented foods, such as cheese, wine, beer and cured meats. “

Professor Raul R. Gainetdinov, Director of the Institute of Translational Biomedicine and Academic Supervisor of the University Hospital of St. Petersburg

Most TAARs have been described mainly in the olfactory epithelium of the nose and considered olfactory receptors that detect innate odors (decaying tissue, pheromones, predators). However, TAARs are also found in certain areas of the brain and are involved in the regulation of our emotions, as discovered by scientists at the University’s Institute of Translational Biomedicine. The experiments revealed that “knockout” TAAR5 mice with a “switched off” gene encoding the TAAR5 protein exhibit antidepressant-like and anxiety-like behaviors and alterations in brain transmission of serotonin.

Further detailed investigations focused on how TAAR5 can affect dopamine neurons in the substantia nigra of the brain. Some neurodegenerative disorders, including Parkinson’s disease, are associated with the loss of dopaminergic neurons. The research results were rather unexpected, the scientists say.

“The number of dopaminergic neurons in the substantia nigra and dopamine content increased by 30% in TAAR5-free mice compared to wild animals. Such an increase in the number of dopamine neurons can occur during development or via alterations in neurogenesis of the Adult: Some neurons are known to form in neurogenic areas of the brain such as the subventricular zone (SVZ) and the subgranular zone (SGZ) in adult mammals.

The analysis showed that TAAR5 is present in these canonical neurogenic areas as well as in the potentially neurogenic area surrounding the 3rd ventricle. It is also known that adult neurogenesis can be regulated via serotonin receptors, dopamine receptors and adrenoceptors and can be increased during antidepressant treatment. In fact, we found that TAAR5 knockout mice show increased neurogenesis in adults, ”says Professor Gainetdinov.

TAARs can act as intra-cerebral “olfactory” sensors to detect decarboxylated amino acids and thus provide a neurotransmitter mechanism to trigger a neurogenic reaction in response to various pathological processes in the brain. Therefore, TAARs can not only modulate emotional behaviors, but also regulate adult neurogenesis. Targeting TAAR5 may provide a new treatment opportunity for neurodegenerative disorders, including Parkinson’s and Alzheimer’s disease.

Yet much remains to be done. Scientists are looking to evaluate future TAAR5 selective antagonists on adult neurogenesis. Further detailed investigations are needed to elucidate the molecular mechanism leading to an increase in the number of dopaminergic neurons in the substantia nigra of TAAR5 knockout mice.