Japanese Researchers Discover New Biomarker For Schizophrenia Using Hydrogen Sulphide in Human Hair
Medical researchers from RIKEN Brain Science Institute in Tokyo have discovered a biomarker for schizophrenia
. Working with animal models, postmortem human brains, and people with schizophrenia
, the researchers discovered that a subtype of schizophrenia
is related to abnormally high levels hydrogen sulfide in the brain. Studies showed that this abnormality likely results from a DNA-modifying reaction during development that lasts throughout life. In addition to providing a new direction for research into drug therapies, higher-than-normal levels of the hydrogen sulfide-producing enzyme can act as biomarker for this type of schizophrenia
Diagnosing brain or behavioral disorders is easier when a reliable and objective marker can be found.
In the case of schizophrenia
, it has been known for more than a few decades that it is associated with an abnormal startle response. Normally, individuals are not startled as much by a burst of noise if a smaller burst called a prepulse comes a little bit earlier. This phenomenon is called prepulse inhibition (PPI) because the early pulse inhibits the startle response. In people with schizophrenia, PPI is lowered, meaning that their startle response is not dampened as much as it should be after the prepulse.
Although the PPI test is a good behavioral marker, it cannot directly help us understand the biology behind schizophrenia
. It was however the starting point that led to current discoveries.
The medical researchers at RIKEN CBS began first looked for differences in protein expression between strains of mice that exhibit extremely low or extremely high PPI. Ultimately, they found that the enzyme Mpst was expressed much more in the brains of the mouse strain with low PPI than in the strain with high PPI. Knowing that this enzyme helps produce hydrogen sulfide, the team then measured hydrogen sulfide levels and found that they were higher in the low-PPI mice.
Dr Takeo Yoshikawa, co author of the study commented in a phone interview with Thailand Medical
News. Nobody has ever thought about a causal link between hydrogen sulfide and schizophrenia
.Once we discovered this, we had to figure out how it happens and if these findings in mice would hold true for people with schizophrenia
Initially to be sure that Mpst was the culprit, the researchers created an Mpst knockout version of the low-PPI mice and showed that their PPI was higher than that in regular low-PPI mice. Thus, reducing the amount of Mpst helped the mice become more normal. Next, they found that MPST gene expression was, indeed, higher in postmortem brains from people with schizophrenia
than in those from unaffected people. MPST protein levels in these brains also cor
related well with the severity of premortem symptoms.
Once the team had enough information to look at MPST expression as a biomarker for schizophrenia
, they examined hair follicles from more than 150 people with schizophrenia and found that expression of MPST mRNA was much higher than people without schizophrenia
. Even though the results were not perfect indicating that sulfide stress does not account for all cases of schizophrenia
MPST levels in hair could be a good biomarker for schizophrenia
before other symptoms
Factors as to whether a person develops schizophrenia is related to both their genetics and the environment. Testing in mice and postmortem brains indicated that high MPST levels were associated with changes in DNA that lead to permanently altered gene expression. So the next step was for the team to search for environmental factors that could result in permanently increased MPST production.
As hydrogen sulfide can actually protect against inflammatory stress, the group hypothesized that inflammatory stress during early development might be the root cause.
Dr Takeo Yoshikawa further commented "We found that anti-oxidative markers including the production of hydrogen sulfide that compensate against oxidative stress and neuroinflammation during brain development were correlated with MPST levels in the brains of people with schizophrenia.
Dr Yoshikawa proposes that once excess hydrogen sulphide production is primed, it persists throughout life due to permanent epigenetic changes to DNA, leading to "sulfide stress"-induced schizophrenia
Conventional treatments for schizophrenia
focus on the dopamine and serotonin system in the brain. Because these drugs are not very effective and have side effects, says that pharmaceutical companies have abandoned the development of new drugs.
"A new approach is needed for the development of new drugs. Presently about 32 percent of individuals with schizophrenia
are resistant to dopamine D2-receptor antagonist treatment. Our findings provide a new direction for drug development, and we are at present testing whether inhibiting the synthesis of hydrogen sulphide can alleviate symptoms in animal models of schizophrenia
.” commented Dr Takeo Yoshikawa
Ide et al. (2019) Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology. EMBO Molecular Medicine
. DOI: 10.15252/emmm.201910695