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Israeli Researchers Discover Link Between Brain Cell Protein Deficiency And Schizophrenia

Tel Aviv University researchers find inhibition of a basic cellular process may contribute to the mysterious disease.

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Artistic view of how the world feels like with schizophrenia / Wikipedia

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.

“We 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.”

 

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.

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.

 

1 Comment

1 Comment

  1. jewishbusiness

    January 1, 2014 at 1:34 am

    ​We publish here a comment received by mail:

    Are You Schizophrenic?
    Most people consider that psychiatry’s main function is to treat patients with severe, even life–threatening mental conditions. The most pronounced is that condition first called dementia praecox by German psychiatrist Emil Kraepelin in the late 1800’s, and labeled “schizophrenia” by Swiss psychiatrist Eugen Bleuler in 1908.
    Robert Whitaker, author of Mad in America, says the patients that Kraepelin diagnosed with dementia praecox were actually suffering from a virus, encephalitis lethargica (brain inflammation causing lethargy) which was unknown to doctors at the time.
    Psychiatry never revisited Kraepelin’s material to see that schizophrenia was simply an undiagnosed and untreated physical problem. “Schizophrenia was a concept too vital to the profession’s claim of medical legitimacy. The physical symptoms of the disease were quietly dropped. What remained, as the foremost distinguishing features, were the mental symptoms: hallucinations, delusions, and bizarre thoughts,” says Whitaker. Psychiatrists remain committed to calling “schizophrenia” a mental disease despite, after a century of research, the complete absence of objective proof that it exists as a physical brain abnormality.
    Today, psychiatry clings tenaciously to antipsychotics as the treatment for “schizophrenia,” despite their proven risks and studies which show that when patients stop taking these drugs, they improve.
    Professor Thomas Szasz states that “schizophrenia is defined so vaguely that, in actuality, it is a term often applied to almost any kind of behavior of which the speaker disapproves.”
    Pediatric neurologist Fred Baughman, Jr., wrote: “The fact of the matter is—and a fact to which the country had better wake up—is that there is no abnormality to be found in any of psychiatry’s ‘diseases’—not in infants, not in toddlers, not in preschoolers, not at any age. Without invented ‘diseases,’ the psychiatric–pharmaceutical cartel would have nothing to treat.”
    These are normal people with medical, disciplinary, educational, or spiritual problems that can and must be resolved without recourse to drugs. Deceiving and drugging is not the practice of medicine. It is criminal.
    Bear in mind that the drug “treatments” being prescribed are for “disorders” that are not physical illnesses—essentially, they are being prescribed for something that does not exist.
    Any medical doctor who takes the time to conduct a thorough physical examination of a child or adult exhibiting signs of what a psychiatrist calls Schizophrenia can find undiagnosed, untreated physical conditions. Any person labeled with so-called Schizophrenia needs to receive a thorough physical examination by a competent medical—not psychiatric—doctor to first determine what underlying physical condition is causing the manifestation.
    Any person falsely diagnosed as mentally disordered which results in treatment that harms them should file a complaint with the police and professional licensing bodies and have this investigated. They should seek legal advice about filing a civil suit against any offending psychiatrist and his or her hospital, associations and teaching institutions seeking compensation.
    No one denies that people can have difficult problems in their lives, that at times they can be mentally unstable, subject to unreasonable depression, anxiety or panic. Mental health care is therefore both valid and necessary. However, the emphasis must be on http://cchrstl.org/alternatives.shtml that improve and strengthen individuals and thereby society by restoring people to personal strength, ability, competence, confidence, stability, responsibility and spiritual well–being. Psychiatric drugs and psychiatric treatments are not workable.
    For more information, download and read the free CCHR report, Schizophrenia—Psychiatry’s For Profit ‘Disease’ – available athttp://www.cchrstl.org/schizophrenia.shtml.

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