Unfortunately, modern psychiatry knows relatively little about the causes of schizophrenia. In fact, it was only recognized as being a medical condition in the past several decades. Because so little is understood about the illness, there is not even an objective test to detect its presence. Doctors must instead rely the patient’s symptoms to make a diagnosis. In addition, the standard treatment for schizophrenia – medications known as antispsychotics – work less than half the time and eventually lose their effectiveness, even in the patients who respond to them.
In order to tackle the very difficult problem of understanding what causes schizophrenia, Professor Illana Gozes has been working with a team of students and colleagues to study a newly-discovered pathway that, in part, may cause this illness. She believes that by studying this pathway, the disease can be better diagnosed and more effectively treated.
The pathway that the team studied was what is known as autophagy. Autophagy, the team says, is like a “housekeeping service” for cells. This process cleans up any unneeded and improperly functioning cellular components. To clear these components out, a membrane called a phagophore surrounds and swallows them up, forming what is known as a autophagosome. This body then shuttles its contents to another body called a lysosome. It then merges with the lysosome, allowing the lysosome to digest its contents for disposal or reuse. Not surprisingly, autophagy is very important in maintaining cellular health. And, when the process becomes blocked, it is very detrimental to the cell, eventually leading to cell death. Several past studies, in fact, have linked blocked authophagy to the death of brain cells that occurs in Alzheimer’s disease.
Because brain-cell death also occurs in schizophrenia, this prompted Gozes and her team to check to see if blocked authophagy might play a role in this condition.
What they found was RNA evidence of declining levels of a protein called beclin 1 in a region of the brain called the hippocampus. The hippocampus is important in memory and learning. Since beclin 1 is essential in starting the process of autophagy, if there is not enough of it, it could block this process, they say. They further theorize that drugs capable of boosting levels of beclin 1, and thus restarting the process of autophagy, may be a new way to treat schizophrenia.
The next step that the researchers took was to examine the levels of beclin 1 in the blood of patients with schizophrenia. But, they did not find any differences in its levels, suggesting that the deficit is limited to the hippocampus. What they did find, however, is that the patients’ white blood cells were deficient in another protein, activity-dependent neuroprotective protein (ADNP). This protein, which was discovered by Gozes, has been found to be important for brain function. Previous studies have shown problems with its regulation in the brains of patients with schizophrenia.
The research team theorizes that levels of ADNP may become elevated in order to protect the brain when the process of autophagy fails. If this is confirmed, then blood tests for ADNP levels could potentially be used to diagnose schizophrenia.
The researchers further studied how ADNP is involved in autophagy by running tests on mouse brains. What they found was that in mice ADNP interacts with another key protein called LC3 in the regulation of autophagy.
Gozes has been able to develop a potential drug for schizophrenia called NAP, which is a protein fragment that she was able to cut away from ADNP. NAP appears to protect nerve cells in a similar way to what ADNP does. In studies, NAP appeared to improve the ability of schizophrenic patients to cope with their daily activities. Gozes and her team hope that it is the first of many discoveries which they will make that will improve the diagnosis and treatment of this illness.
The study looking into blocked autophagy as a possible cause for schizophrenia was published in Nature‘s Molecular Psychiatry.
By Nancy Schimelpfening