Teamwork between a brain chemical that regulates mood and a longevity protein reduces the risk of age-related neurodegenerative diseases such as Alzheimer’s and Parkinson’s as well as psychiatric disorders such as clinical depression and autism, a new study by the Tata Institute of Fundamental Research (TIFR) has found. This has paved the way for novel therapeutic strategies.

A 12-member team jointly led by professors Vidita Vaidya and Ullas Kolthur-Seetharam from TIFR’s Department of Biological Sciences has found that serotonin – a major neurotransmitter that transmits chemical signals from one brain cell to another – interacts with the longevity protein Sirtuin1 (SIRT1) to generate new mitochondria in neurons or brain cells, control their production and also increase the energy fuel (ATP) in neurons.

The study, ‘Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axis’, was published in Proceedings of the National Academy of Sciences of the United States of America, last week.

Mitochondria are known as the powerhouse of all cells because they produce 90% of the chemical energy that our body needs to survive. They are the key parts of neurons that can help them successfully survive an entire lifetime.

Previous studies have shown that both serotonin and SIRT1 are independently linked with survival of mitochondrial neurons. “But no one thought that serotonin and SIRT1 come together to produce new mitochondria and increase energy production, both of which are important for normal and healthy functioning of neurons,” said Vaidya, senior author and professor, TIFR. “More important, however, is that serotonin buffers toxic stress via SIRT1 and mitochondria that could otherwise kill the neurons.”

Researchers said while serotonin, SIRT1 and mitochondria decrease as one gets old, they also get perturbed in neurodegenerative diseases such as dementia, Alzheimer’s and Parkinson’s. Repairing or restoring mitochondrial function, said researchers, can reduce the toxic effects of stress and delay neurodegenerative diseases.

“This research is a great jump in explaining how, and why antidepressants may not only help patients recover, but also protect the brain. This is critical, as recurrent episodes of depression are often linked to deterioration in brain function,” said Dr Sanjeev Jain, professor, National Institute of Mental Health and Neurosciences, Bengaluru, who was not involved in the study. “The findings allow us to think of more strategies to invent/discover new ways to protect the brain in times of distress.”

The present study, using old mice aged 15 months, has shown that the interaction between serotonin 5-HT2A receptor – it is essential for learning and cognition – and SIRT1 is essential to keep mitochondria healthy in neurons.

“Many pharmaceutical companies are investing millions of dollars in looking for therapies for aging, neurodegenerative diseases and psychiatric disorders that either target SIRT1, which will affect the whole body or serotonin that will affect neurons,” said Kolthur-Seetharam, co-senior author and associate professor, TIFR. “A treatment targeting both or titrating the dosage may yield more benefit. Our results present an opportunity to develop new treatments using existing molecules or design new molecules that hit both together.”

“The findings are extremely novel as, to date, this is the first study to implicate in a mechanistic manner mitochondrial function as a key effector of the neurotransmitter serotonin in the brain,” said Carmen Sandi, professor of neuroscience, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, Switzerland, who was not involved in the study. “The findings are also highly significant as they offer completely new insights about how the brain works, providing a key role for mitochondria among the processes whereby a key neurotransmitter affects brain function.”

Improper functioning of mitochondria due to imbalance in serotonin and disturbance in SIRT1 has also been more recently linked with anxiety, depression, schizophrenia, and autism.

“This link can be exploited in future to better understand how serotonin-reuptake inhibitors, still a leading therapy choice, works and how new, repurposed nutraceuticals (from Ayurveda and other traditional schools) can be harnessed to increase levels of serotonin in the brain to combat these conditions,” said Aditi Bhattacharya, neuroscientist, Centre for Brain Development and Repair, inStem, Bengaluru, who was not involved in the study.

First Published: May 15, 2019 01:19 IST