New research published in Molecular Psychiatry has examined the potential role of novel proteins in the future treatment of schizophrenia. Disrupting the degradation of a specific protein may be the key.
Schizophrenia is a highly disruptive condition that affects around 1 in 100 people during the course of their lifetime. It is characterized by a disconnection between thoughts, behaviors, and emotions.
Despite impacting roughly 1 percent of people in the United States, its exact causes are not fully understood, and it cannot yet be cured. In fact, there have been no significant breakthroughs in the treatment of schizophrenia for over half a century.
Current drug treatment focuses primarily on reducing symptoms, with the most commonly used drugs being antipsychotics. These medications do not work well for some patients, and there are significant side effects – especially if taken over many years.
Although the causes behind the condition are still a mystery, there are some factors that are known to play a part: one of which is genetics. For instance, schizophrenia affects 10 percent of people with a first-degree relative who has the condition, marking a 10-fold increase in risk compared with the general population.
Over the years, certain genes and proteins have been found to play a role in the development of schizophrenia. Of particular interest is a protein called disrupted in schizophrenia 1 (DISC1), which is coded by a gene of the same name.
This protein has a range of vital roles, including regulation of cell proliferation, differentiation, and migration, and nerve growth. Individuals with hereditary schizophrenia have lower levels of functioning DISC1.
A recent study, carried out at the University of Glasgow in the United Kingdom, investigated a way to maintain higher levels of this protein in the body.
Lead author George Baillie, a professor of molecular pharmacology at the university’s Institute of Cardiovascular and Medical Sciences, says, “We looked at the turnover of DISC1 in the brain and found it was rapidly made and then degraded by brain cells.”
“We thought, if we can stop the natural destruction of DISC1, people with low levels would see it naturally increase.”
To do this, the researchers investigated the role of an F-box protein called FBXW7. F-box proteins play a part in ubiquitination – that is, the addition of a small molecule called ubiquitin to proteins. Ubiquitin labels a protein for the attention of enzymes, signaling its degradation. In other words, ubiquitin marks a protein for death. Specifically, FBXW7 tags DISC1 for destruction.
They hypothesized that if they could prevent FBXW7 and DISC1 from interacting, they might be able to minimize the breakdown of DISC1, increasing levels of the protein overall.
For this study, they took cells from patients with schizophrenia and converted them into brain cells. Next, they added an inhibitory peptide – namely, a short chain of amino acids – that prevents FBXW7 from breaking down DISC1.
As expected, the introduction of the novel peptide did reduce the breakdown of DISC1, keeping it at a normal level.
“Using our peptide, we can now restore DISC1 concentrations in psychiatric patient derived brain cells back to the levels of control subjects. […] We are hopeful that our peptide can be a stepping stone toward a novel therapeutic in the future to counteract this unmet need.”
Prof. George Baillie
The findings are exciting, and, as schizophrenia treatment has not advanced for such a long time, a glimmer of hope is exactly what the field needs. However, the excitement must be treated with caution; there is a long distance between these results and converting them into a usable drug.
As Prof. Baillie makes clear, “As positive as our discovery is, we have some way to go between laboratory findings and the clinical application, but we are hopeful that our research is the first step on a journey towards a potential new drug treatment option for a range of psychiatric illnesses.”