BioWorld International Correspondent

LONDON - Scientists have identified a novel biochemical pathway underpinning the development of severe mental illnesses such as schizophrenia and bipolar disorder. The new pathway links an enzyme not previously known to have a role in mental illness with the product of a gene that had been linked to schizophrenia.

The enzyme belongs to the class known as phosphodiesterases. Drug designers already are targeting other members of that family with the aim of developing treatments for disorders such as asthma and chronic obstructive pulmonary disease, raising hopes that it may be possible to apply similar approaches to therapies for severe mental illnesses.

David Porteous, professor of medical genetics at the University of Edinburgh, told BioWorld International: "This discovery sheds light on a very poorly understood subject, and one that is of huge importance because schizophrenia and bipolar disorder affect one in 50 of the population worldwide. We may be some way off from a cure, but we are now a lot closer to understanding the underlying problem, which gives us a much better chance of developing more effective and safer treatments."

Porteous, together with colleagues in Edinburgh, and collaborating teams in Glasgow, Paris and Edinburgh, and at Merck Sharp and Dohme Ltd. in Harlow, reports the findings in the Nov. 18, 2005, issue of Science in a paper titled, "DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling." J. Kirsty Millar and Benjamin S. Pickard are the joint first authors of the paper.

Five years ago, Porteous and his colleagues discovered that the gene they called DISC1 (for disrupted in schizophrenia) appeared to play a role in schizophrenia. An abnormal version of the gene was inherited by affected members of a large Scottish family, several of whom had schizophrenia, bipolar affective disorder or recurrent major depression. But no one knew how or why DISC1, when faulty, caused those conditions.

The group set out to find out. "Our investigations showed that the protein produced by DISC1 was probably a scaffold' protein to which other proteins attach, forming a functional complex," Porteous said. "We did biochemical studies to find out what those other proteins were, and one of them turned out to be a specific phosphodiesterase."

The phosphodiesterase in question was called PDE4B1. It was already known to be important in regulating the level of the key signaling molecule cyclic adenosine monophosphate (cAMP). Experiments showed that DISC1 binds PDE4B1. When cAMP levels rise, DISC1 and PDE4B1 dissociate and PDE4B1 becomes activated.

Although PDE4B1 had never previously been associated with mental illness, some studies in animals did point to a neurological role. For example, mutations in the equivalent gene in Drosophila result in learning and memory defects. In mice, animals lacking functional PDE4B1 behave as they do when they have been treated with antidepressants. In addition, PDE4 is the physiological target for the antidepressant rolipram.

What clinched the role of PDE4B1 for Porteous and his colleagues, however, was the discovery that, in patients with schizophrenia, the gene encoding that protein was sometimes damaged.

Porteous said, "We then had a link between the two proteins at the functional level — they interacted and regulated each other's activity — and we had the evidence from family studies that damage to either DISC1 or PDE4B1 was associated with an elevated risk of major mental illness."

The finding confirmed yet again, he added, that DISC1 is a "really important player" in terms of genetic risk of mental illness.

Being an enzyme, PDE4B1 could be an ideal therapeutic target. "This is a well-known class of proteins," Porteous said. "There are already drugs being developed that modulate the activity of other members of the phosphodiesterase family, for the treatment of asthma and stroke, for example. This gives us hope that the pharmaceutical industry may be able to adapt its work in related areas to bear intelligently on the area of mental illness."

Future work for the group will include working out exactly how DISC1 and PDE4B1 interact in the cell, and what the cellular consequences are. "We will also look at ways of modifying this interaction, with a view to being able to correct the biochemical imbalance that is found in patients with schizophrenia or bipolar affective disorder," Porteous said.