29 Oct Subtype of Schizophrenia Can Be Identified by Enzyme in Hair
MedicalResearch.com Interview with:
Dr. Takeo Yoshikawa MD PhD
RIKEN Center for Brain Science
MedicalResearch.com: What is the background for this study? What are the main findings?
- Currently available drugs for schizophrenia are the dopamine D2 receptor blockers.
These compounds were serendipitously discovered over half-century ago.
But about 30% of schizophrenia are resistant to the dopamine D2 receptor blockers.
In spite of these conditions, pharmaceutical companies have abandoned the development
of new drugs. This is because we do not know the principle of drug design.
- Therefore, we need to understand the molecular underpinning of as-yet unknown schizophrenia pathophysiology.
Schizophrenia is diagnosed by only patients’ symptoms, not by biological examination.
To search for biological underpinning for schizophrenia using experimental animals,
we thought that we should examine an endophenotype (biological trait) relevant to schizophrenia.
Then we targeted prepulse (PPI) performance.
- Here, dampened PPI is considered as a biological marker of psychiatric disorders, typically of schizophrenia.
Importantly, PPI can be measured using the same behavioral paradigm between experimental animals and human.
- C57BL/6 (B6) inbred mouse shows higher (better) prepulse inhibition (PPI) performance, while C3H/He (C3H) inbred mouse shows lowered (worse ) PPI. We premised that C3H mouse is “schizophrenia-prone” and B6 is not. To know the molecular basis for differential PPI levels between the two inbred mouse strains, we performed comprehensive protein expression level analysis (proteomics analysis) using the brains of B6 and C3H mice.
- The expression levels of Mpst, a hydrogen sulfide (H2S)-producing enzyme, is elevated in C3H mouse compared to B6 mouse. Biochemical analysis also supported the elevated H2S production in C3H mouse compared to B6.
- The examination of human samples including postmortem brains, iPS-derived neural stem cells (neurospheres) and hair follicle cells, gave evidence that H2S production system is indeed up-regulated in schizophrenia.
MedicalResearch.com: What are the main findings?
- The previous studies regarding H2S have mainly focused on the beneficial role of H2S. This is because organisms including mouse and human synthesize H2S endogenously. Our study shows that H2S, when it is excessively synthesized, brings a detrimental effect in the brain.
- A functional consequence elicited by excess hydrogen sulfide production, or how brain function is damaged by excess H2S production, is that excess H2S hampers energy metabolism in the brain.
- An origin or cause that induces the hyper H2S production state is, epigenetic changes of genome DNA (DNA methylation), not inherent genetic (genome) polymorphisms (variants). Epigenetic changes can be elicited by subtle brain insults including viral infection of pregnant mother. This scenario conforms to the so-called “neurodevelopmental hypothesis of schizophrenia genesis”, and our work deciphered one of concrete entities (mechanisms) underlying this hypothesis.
- Our study provides a quite novel paradigm for schizophrenia pathophysiology, and is hoped to provide a new principle for drug design.
MedicalResearch.com: What should readers take away from your report?
Response: Development of inhibitors of H2S-producing enzymes could be a boon for schizophrenia patients, in particular those who are not satisfied with current drugs.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: We call the hyper production state of H2S as “sulfide stress”.By further delineating the precise mechanisms for “sulfide stress”,
for example identifying the proteins that are susceptible to “sulfide stress”, we could know additional druggable targets for schizophrenia.
MedicalResearch.com: Is there anything else you would like to add?
Response: Schizophrenia is thought to be etiologically heterogeneous.
Examination of MPST (a H2S synthesizing enzyme) expression in hair follicle cells could identify the subgroup of schizophrenia
suffering from “sulfide stress”, or stratify schizophrenia.We need just around 10 hairs, and such collection should be noninvasive.
This could lead to precision medicine of schizophrenia.
Thank you very much again for your interest in our work.
Masayuki Ide, Tetsuo Ohnishi, Manabu Toyoshima, Shabeesh Balan, Motoko Maekawa, Chie Shimamoto‐Mitsuyama, Yoshimi Iwayama, Hisako Ohba, Akiko Watanabe, Takashi Ishii, Norihiro Shibuya, Yuka Kimura, Yasuko Hisano, Yui Murata, Tomonori Hara, Momo Morikawa, Kenji Hashimoto, Yayoi Nozaki, Tomoko Toyota, Yuina Wada, Yosuke Tanaka, Tadafumi Kato, Akinori Nishi, Shigeyoshi Fujisawa, Hideyuki Okano, Masanari Itokawa, Nobutaka Hirokawa, Yasuto Kunii, Akiyoshi Kakita, Hirooki Yabe, Kazuya Iwamoto, Kohji Meno, Takuya Katagiri, Brian Dean, Kazuhiko Uchida, Hideo Kimura, Takeo Yoshikawa. Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology. EMBO Molecular Medicine, 2019; DOI: 10.15252/emmm.201910695
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