Researchers at Tel Aviv University say they have discovered that an important cell-maintenance process—autophagy—is reduced in the brains of schizophrenic patients. The findings in the study (“Autophagy has a key role in the pathophysiology of schizophrenia”), published in Molecular Psychiatry, could advance the understanding of schizophrenia and enable the development of new diagnostic tests and drug treatments for the disease, according to the scientists.
“We discovered a new pathway that plays a part in schizophrenia,” said Illana Gozes, Ph.D., the Lily and Avraham Gildor Chair for the Investigation of Growth Factors, the director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine, and a member of the Sagol School of Neuroscience at Tel Aviv University. “By identifying and targeting the proteins known to be involved in the pathway, we may be able to diagnose and treat the disease in new and more effective ways.”
Autophagy is like the cell's housekeeping service, cleaning up unnecessary and dysfunctional cellular components. The process, in which a membrane engulfs and consumes the clutter, is essential to maintaining cellular health. But when autophagy is blocked, it can lead to cell death. Several studies have tentatively linked blocked autophagy to the death of brain cells seen in Alzheimer's disease.
“Several key proteins govern the autophagy pathway including beclin1 and microtubule associated protein 1 light chain 3 (LC3),” wrote the investigators. “Here, we show a brain-specific reduction in beclin1 expression in postmortem hippocampus of schizophrenia patients, not detected in peripheral lymphocytes.”
More specifically, Dr. Gozes’ team found RNA evidence of decreased levels of beclin 1 in the hippocampus of schizophrenia patients, a brain region central to learning and memory. Beclin 1 is central to initiating autophagy. Its deficit suggests that the process is indeed blocked in schizophrenia patients. Developing drugs to boost beclin 1 levels and restart autophagy could offer a new way to treat schizophrenia, the researchers say.
“It is all about balance,” noted Dr. Gozes. “Paucity in beclin 1 may lead to decreased autophagy and enhanced cell death. Our research suggests that normalizing beclin 1 levels in schizophrenia patients could restore balance and prevent harmful brain-cell death.”
The scientists also looked at protein levels in the blood of schizophrenia patients. They found no difference in beclin 1 levels, suggesting that the deficit is limited to the hippocampus. But the researchers also discovered increased levels of another protein, activity-dependent neuroprotective protein (ADNP), which has been shown to be essential for brain formation and function, in the patients' white blood cells. Previous studies have shown that ADNP is also deregulated in the brains of schizophrenia patients.
The researchers think the body may boost ADNP levels to protect the brain when beclin 1 levels fall and autophagy is derailed. ADNP, then, could potentially serve as a biomarker, allowing schizophrenia to be diagnosed with a simple blood test.
To further explore the involvement of ADNP in autophagy, the researchers ran a biochemical test on the brains of mice. The test showed that ADNP interacts with LC3. In light of the newfound correlation between autophagy and schizophrenia, they believe that this interaction may constitute part of the mechanism by which ADNP protects the brain.
Dr. Gozes discovered ADNP in 1999 and carved a protein fragment, davunetide (NAP), from it. NAP mimics the protein nerve cell protecting properties. Dr. Gozes subsequently helped develop NAP as a drug candidate. In Phase II clinical trials, she said, NAP improved the ability of schizophrenic patients to cope with daily life. The researchers hope NAP will be just the first of their many discoveries to improve understanding and treatment of schizophrenia.