An enzyme that contributes to the production of hydrogen sulfide in the brain and leaves traces of hair follicles may be an asymptomatic biomarker of schizophrenia

A new study published in EMBO Molecular Medicine suggests that an enzyme that aids in the production of hydrogen sulfide in the brain and leaves traces on human hair may serve as a pre-systemic biomarker for a subtype of schizophrenia.

The researchers suggest that the findings could lead to the creation of a new class of drugs for schizophrenia. Existing therapies that target the brain’s dopamine and serotonin systems are not always effective and may also cause side effects.

“Targeting the metabolic pathway of hydrogen sulfide provides a new therapeutic approach,” conclude the authors, whose research included genetically modified animal models (mice), post-mortem human brain tissue, people with schizophrenia and people with no disease.

The first researcher Dr Takeo Yoshikawa, notes that drug companies have stopped developing new treatments for schizophrenia.

Looking for a more reliable index

The new study investigates the molecular basis of a behavioural marker of schizophrenia based on propanoic inhibition of acoustic reflex shock in humans.

Most people respond to a sudden click with surprise. However, if they hear a lesser click just before, their stronger click causes less annoyance. This is due to the fact that the precursor response (prophylactic inhibition of acoustic reflex shock in humans) inhibits the onset surprise.

For decades, scientists have known that many people with schizophrenia had a lower prophylactic inhibition of acoustic reflection surprise, with their response to sudden noise remaining intense even when preceded by “warning.”

Dr Yoshikawa and his colleagues saw the pre-pulmonary suspension of acoustic reflex shock in humans as the starting point for their research.

They used experimental animals that had different levels of pre-pulmonary acoustic reflex inhibition to investigate protein expression patterns that might match these levels. This study identified the enzyme MPST. The researchers observed that mice with low pre-pulmonary inhibition of acoustic reflex inhibition had higher levels of MPST in the brain compared with mice with high pre-pulmonary inhibition of acoustic reflex inhibition.

MPST, hydrogen sulfide and hair follicles

Knowing that one of the functions of MPST is to boost hydrogen sulfide production, the research team examined the brains of experimental animals and found that hydrogen sulfide levels were higher in those with lower pre-pulmonary acoustic reflex inhibition.

“No one has ever thought of a causal link between hydrogen sulfide and schizophrenia. Once we discovered it, we had to understand how this happens and the findings in mice would apply to people with schizophrenia,” commented Dr Yoshikawa.

After identifying MPST as the “underlying suspect”, the researchers looked for further evidence and found that MPST-deficient mice had a higher pre-pulmonary inhibition of acoustic reflex shock than normal mice.

This result indicated that the reduction of MPST may be a way of restoring prophylactic inhibition of acoustic reflex shock.

In the next phase, the researchers compared post-mortem brain tissue from people with and without schizophrenia.

The comparison revealed stronger expression in the gene encoding MPST in the brain tissue of people with schizophrenia. It also appeared that Mpst levels were consistent with the severity of the symptoms before death.

In another series of tests, the researchers examined hair follicles from 149 people with schizophrenia and 166 who did not have the disease. People with schizophrenia were found to have higher levels of the protein that transmits information from the gene encoding Mpst in the hair follicles.

Epigenetic origin of schizophrenia

The chances of developing schizophrenia involve gene-environment interaction. An example of this interaction is epigenetic changes that may alter gene expressions such as their activation and inactivation.

Experiments in experimental animals and post-mortem human brain tissue showed that higher levels of Mpst were associated with greater alterations in DNA, resulting in permanent changes in gene expression. Knowing this, the research team looked for environmental factors that could cause permanent growth of Mpst.

“We found that antioxidant markers – including hydrogen sulfide – that compensate for antioxidant stress and neuroinflammation in brain development were related to Mpst levels in the brains of people with schizophrenia,” said Dr. Yoshikawa.

Responding to what this may mean for the origins of schizophrenia, Dr. Yoshikawa explains that when an epigenetic change alters the production of hydrogen sulfide, that change lasts for the rest of one’s life. He calls this schizophrenia as due to “sulfide stress”.

“Our results provide a new beginning for drug design, and we are now examining whether inhibiting hydrogen sulfide synthesis could alleviate symptoms in animal models of schizophrenia,” concludes the researcher.