Toward a Molecular Explanation for Schizophrenia


December 30, 2013
Brain & Behavior, Health

Surprisingly little is known about schizophrenia. It was only recognized as a medical condition in the past few decades, and its exact causes remain unclear. Since there is no objective test for schizophrenia, its diagnosis is based on an assortment of reported symptoms. The standard treatment, antipsychotic medication, works less than half the time and becomes increasingly ineffective over time.

Now, Prof. Illana Gozes — 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 — has discovered that an important cell-maintenance process called autophagy is reduced in the brains of schizophrenic patients. The findings, published in Nature’s Molecular Psychiatry, advance the understanding of schizophrenia and could enable the development of new diagnostic tests and drug treatments for the disease.

Toward a Molecular Explanation for SchizophreniaWe discovered a new pathway that plays a part in schizophrenia,” said Prof. Gozes. “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.”

Graduate students Avia Merenlender-Wagner, Anna Malishkevich, and Zeev Shemer of TAU, Prof. Brian Dean and colleagues of the University of Melbourne, and Prof. Galila Agam and Joseph Levine of Ben Gurion University of the Negev and Beer Sheva’s Psychiatry Research Center and Mental Health Center collaborated on the research.

Mopping up

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.

Brain-cell death also occurs in schizophrenics, so Prof. Gozes and her colleagues set out to see if blocked autophagy could be involved in the progression of that condition as well. They found RNA evidence of decreased levels of the protein 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,” said Prof 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.”

Next, the researchers 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 found increased levels of another protein, activity-dependent neuroprotective protein (ADNP), discovered by Prof. Gozes and 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.

An illuminating discovery

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, another key protein regulating autophagy — an interaction predicted by previous studies. 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.

Prof. Gozes discovered ADNP in 1999 and carved a protein fragment, NAP, from it. NAP mimics the protein nerve cell protecting properties. In follow-up studies Prof. Gozes helped develop the drug candidate davunetide (NAP). In Phase II clinical trials, davunetide (NAP) improved the ability of schizophrenic patients to cope with daily life. A recent collaborative effort by Prof. Gozes and Dr. Sandra Cardoso and Dr. Raquel Esteves showed that NAP improved autophagy in cultures of brain-like cells. The current study further shows that NAP facilitates the interaction of ADNP and LC3, possibly accounting for NAP’s results in schizophrenia patients. The researchers hope NAP will be just the first of their many discoveries to improve understanding and treatment of schizophrenia.

Toward a Molecular Explanation for Schizophrenia

, , ,

One Response to Toward a Molecular Explanation for Schizophrenia

  1. Byron Sirola December 30, 2013 at 9:37 am #

    Dear Sirs:

    You guys may want to contact U. of Texas (see below) they had conducted very similar test. I lost my son to this illness and just want find a cure. Good Luck.

    SAN ANTONIO — Research from the School of Medicine at The University of Texas Health Science Center at San Antonio suggests the exciting possibility of using cell transplants to treat schizophrenia.

    Cells called “interneurons” inhibit activity within brain regions, but this braking or governing function is impaired in schizophrenia. Consequently, a group of nerve cells called the dopamine system go into overdrive. Different branches of the dopamine system are involved in cognition, movement and emotions.

    “Since these cells are not functioning properly, our idea is to replace them,” said study senior author Daniel Lodge, Ph.D., assistant professor of pharmacology in the School of Medicine.

    Transplant restored normal function

    Dr. Lodge and lead author Stephanie Perez, graduate student in his laboratory, biopsied tissue from rat fetuses, isolated cells from the tissue and injected the cells into a brain center called the hippocampus. This center regulates the dopamine system and plays a role in learning, memory and executive functions such as decision making. Rats treated with the transplanted cells have restored hippocampal and dopamine function.

    Stem cells are able to become different types of cells, and in this case interneurons were selected. “We put in a lot of cells and not all survived, but a significant portion did and restored hippocampal and dopamine function back to normal,” Dr. Lodge said.

    ‘You can essentially fix the problem’

    Unlike traditional approaches to treating schizophrenia, such as medications and deep-brain stimulation, transplantation of interneurons potentially can produce a permanent solution. “You can essentially fix the problem,” Dr. Lodge said. “Ultimately, if this is translated to humans, we want to reprogram a patient’s own cells and use them.”

    After meeting with other students, Perez brought the research idea to Dr. Lodge. “The students have journal club, and somebody had done a similar experiment to restore motor deficits and had good results,” Perez said. “We thought, why can’t we use it for schizophrenia and have good results, and so far we have.”

    The study is in Molecular Psychiatry.

    ###
    This work was supported by a mental health research grant from the Hogg Foundation and an R01 grant (MH090067) and F31 grant (MH098564) from the National Institutes of Health. Representative images were generated in the Core Optical Imaging Facility, which is supported by The University of Texas Health Science Center at San Antonio, NIH-NCI P30 CA54174 (The Cancer Therapy & Research Center at The University of Texas Health Science Center at San Antonio) and NIH-NIA P01AG19316.

    Hippocampal interneuron transplants reverse aberrant dopamine system function and behavior in a rodent model of schizophrenia
    SM Perez and DJ Lodge
    Molecular Psychiatry (2013), 1-6
    Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center, 7703 Floyd Curl Drive, MC 7764, San Antonio, TX 78229, USA.

Leave a Reply

* Copy This Password *

* Type Or Paste Password Here *