Study shows potential of monitoring and inhibiting HDAC proteins.
Laboratory experiments and data from people affected by schizophrenia suggest that tracking blood levels of a particular protein involved in gene regulation may open new possibilities for disease diagnosis. In addition, modulating its activity with drugs could lead to individualized treatments. An international team of researchers led by the German Center for Neurodegenerative Diseases (DZNE), the University Medical Center Goettingen (UMG) and partners in Magdeburg and Munich reported on these findings in the journal PNAS.

Genetic predisposition as well as certain environmental factors such as stress in early life are known to increase the risk for schizophrenia. “Epigenetic processes” are supposed to play a pivotal role in this respect. The term refers to a molecular machinery that regulates the activity of genes – also called “gene expression” – in response to environmental conditions.

The current study investigated both mice with behavioral dysfunctions and people affected by schizophrenia. The mice had been separated from their mothers shortly after birth and thereby exposed to stress in early life. They subsequently developed symptoms alike to those in schizophrenic patients. Elevated levels of “histone–deacetylase 1” (HDAC1), an enzyme involved in epigenetic processes, in the brain’s “prefrontal cortex” caused these symptoms. HDAC1 blood levels were also increased.

A survey of almost 100 adults with schizophrenia that were part of the “PsyCourse cohort” (www.PsyCourse.de) led to similar results. The study participants were asked in detail about their childhood and adolescence. Questioning revealed that some of them had experienced emotional neglect or other traumatic circumstances in early life – conditions commonly linked to a rather poor treatment prognosis. Analysis of blood samples showed increased levels of HDAC1 in these persons.

“Schizophrenia linked to early life stress is associated with specific gene regulation. This is a result of our study. We also see that HDAC1 plays a central role,” says André Fischer, site speaker for the DZNE in Goettingen and professor at the UMG. He points out that blood levels of HDAC1 could possibly serve as a biomarker: “This might help to spot schizophrenia patients that experienced traumas in early life. Identifying these individuals that are particularly resistant to common treatments would be a step toward a personalized therapy tailored to their specific condition. Besides this diagnostic benefit, measuring HDAC1 levels might help to monitor response to treatment.”

In further studies, Fischer and coworkers applied a pharmacological approach. Mice that had been subjected to stress in early life and displayed schizophrenia–like symptoms were treated with “Entinostat”. This drug is currently being tested in clinical studies for use in cancer therapy. It is an inhibitor that blocks the activity of HDAC1. As it turned out, the treatment largely normalized gene expression and alleviated disease symptoms.

“Great care has to be taken when interpreting results from animal experiments in the context of human diseases. This is especially true for such a complex disorder as schizophrenia,” Fischer stresses. “However, our data suggest that drugs that act upon gene activity could possibly mitigate symptoms of schizophrenia. Therefore, I am confident that epigenetics offer great potential for new therapeutic avenues.”