Psychiatric Disorders: What Role Might Brain pH Play?
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To develop effective and safe treatments for a condition, we need to understand which molecular processes are occurring in the body to cause the disease. We can then target or disrupt these processes to either treat symptoms or cure the disease. For conditions of the brain, such as neuropsychiatric and neurodegenerative disorders, this has proven challenging. Despite a wave of advances in neuroscience research techniques over the last few decades, the brain is still somewhat of an elusive character, and treatments for brain disorders are lacking.
However, a closer look at the chemistry of the brain might open up new research avenues. Like all tissues and organs of the body, regulation of the brain's pH level – the balance of acidity and alkalinity – is an important homeostatic function. Research studies have demonstrated a decrease in brain pH – meaning the conditions are more acidic – in neuropsychiatric disorders, leading to the proposal that it is a shared endophenotype for such conditions. As is often the case with new theories, it is somewhat controversial, as it can be challenging to conclude whether such pH changes are a primary feature of the disorder, or an outcome of other factors such as medication. Animal models of brain disorders are useful here, as they can be used experimentally to apply or remove such factors to determine further what role brain pH is having.
You're likely familiar with lactate (or, lactic acid), the chemical by-product of anaerobic respiration that can cause pain in your muscles when you are exercising. Enhanced levels of lactate in the brain have also been observed in neuropsychiatric disorders such as schizophrenia and anxiety disorders.
More about lactate
Lactate is the end-product of the glycolytic pathway, an important metabolic pathway in the body. It comprises a set of enzymatic reactions that ultimately break down glucose into pyruvate, creating adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NADH).
What effect can the enhanced lactate levels have? Recently, a new type of post-translational modification was discovered known as lysine lactylation. Post-translational modifications can cause epigenetic modifications, triggering changes in gene transcription – i.e., turning genes "on" or "off", altering the physiology of a cell. In macrophages, lysine lactylation can be stimulated by lactate. Can lactate have a similar effect in the brain, causing changes to gene transcription?
A new, comprehensive study by researchers at the Institute for Comprehensive Medical Science at Fujita Health University in Japan, in collaboration with Ibaraki University and the Japanese National Institute of Advanced Industrial Science and Technology, explored this query. Their study is published in Cell Reports.
In animal models, the team identified that protein lactylation occurs within neurons of the brain, and that this was positively correlated with lactate levels. The application of stressors known to increase lactate – such as exposure to aggression – enhanced lysine lactylation of histone proteins. The exact role of the protein lactylation in the neurons requires further exploration, but the researchers are confident that their study has opened up a "new area of neuroscience".
Technology Networks interviewed Tsuyoshi Miyakawa, professor at the Division of Systems Medical Science Institute for Comprehensive Medical Science at Fujita Health University, and corresponding author of the study, to learn more about this research and what it means for the neuroscience field.
Molly Campbell (MC): For readers that may be unacquainted with this area of research, please can you discuss the evidence that suggests changes in pH/lactate levels could be a primary feature of neuropsychiatric/neurodegenerative disorders?
Tsuyoshi Mikayawa (TM): First, we found pH/lactate levels were changed in many strains of mouse models of neuropsychiatric disorders. We also found that pH is changed in the post-mortem brains of schizophrenia and bipolar disorder. In fact, there have been many previous research studies that showed pH/lactate is changed in post-mortem brains and also in the brain of living people with various neuropsychiatric/neurodegenerative disorders.
MC: Protein lactylation is a recently discovered post-translational modification. Can you explain what it is and why you wanted to test whether it occurs in brain cells?
TM: In 2019, Zhang et al (Nature) first reported this phenomenon, lactylation, in immune cells (macrophages). Lactylation of a protein called histone changes gene expressions in those cells and changes the properties and functions of those cells. We thought that, if a similar process might be happening in the brain, it would be a big thing, since changes of lactate levels can be commonly seen in various brain disorders. Changes in the properties of neurons by lactylation might be playing some important roles in those disorders.
MC: Can you summarize the key findings of your study that you think are the most important to convey to the public/research community?
A. Lactate, which was considered an energy source of neurons, may also change functions of proteins in the cells in the brain.
B. This phenomenon, lactylation, can be induced by neural activities and by physiologically-relevant stimuli like social stress. When you feel social stress, a lot of proteins in your brain get lactylated and may change their functions.
C. Since lactate levels are known to be changed in the brains of various brain disorders, lactate might be playing important roles in pathophysiology of those disorders.
MC: You state that lactate is believed to have an antidepressant effect. Please can you explain this in the context of the study results?
TM: Lactate has been reported to have an antidepressant effect acutely, but it may exert unknown long-term effects on the functions of the cells in the brain. Such effects could be preferable ones or unpreferable ones. We actually don’t know and so we need to study them in the future.
MC: Are there limitations to this work that you wish to highlight? You emphasize that the results are entirely correlational. Can you expand on this?
TM: Yes, we don’t even know whether lactylation is good or bad. We just know it is happening in our brain.
That’s what we mean by “entirely correlational”.
MC: What are your next research steps?
TM: We need to know the functions of lactylation in the brain. To know them, we need to check one by one by mutating each lactylation site of the proteins and seeing what happens in the cells and in animals, including animal models of those disorders. Then, some of the proteins or molecular pathways that lead to such protein modifications could potentially be the targets of drug discovery for those disorders.
Professor Tsuyoshi Miyakawa was speaking to Molly Campbell, Science Writer for Technology Networks.
Reference: Hagihara H. et al. Protein lactylation induced by neural excitation. Cell Reports. 2021. doi: 10.1016/j.celrep.2021.109820.