Schizophrenia Linked to Defects in the Brain's Autophagy Pathway

A recent paper has linked schizophrenia to inhibition of the cellular degradative process autophagy in the hippocampus segment of the brain.

Autophagy is a self-degradative cellular process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum, and peroxisomes, as well as eliminating intracellular pathogens. Thus, autophagy is generally thought of as a survival mechanism, although its deregulation has been linked to nonapoptotic cell death. Autophagy can be either non-selective or selective in the removal of specific organelles, ribosomes, and protein aggregates, although the mechanisms regulating aspects of selective autophagy are not fully understood. Several key proteins govern the autophagy pathway including beclin1 and microtubule associated protein 1 light chain 3 (LC3).

Currently there are no objective tests for schizophrenia, and its diagnosis is based on an assortment of reported symptoms. In studying the causes of the syndrome investigators at Tel Aviv University (Israel) looked at factors linked to other brain disorders such as Alzheimer's disease, where death of brain cells has been linked to defects in the autophagy pathway.

The investigators analyzed postmortem brain samples from schizophrenia patients. They reported in the December 24, 2013, online edition of the journal Molecular Psychiatry that there was a brain-specific reduction in beclin1 expression in the hippocampus of schizophrenia patients, not detected in peripheral lymphocytes. This was in contrast to the proteins activity-dependent neuroprotective protein (ADNP) and ADNP2, which showed significantly increased expression in lymphocytes from related patients. The increase in ADNP was associated with the initial stages of the disease, and might possibly be a compensatory effect in response to the decline in beclin1.

At the protein level, ADNP was found to co-immunoprecipitate with LC3 suggesting a direct association with the autophagy process and paving the path to novel targets for drug design.

"We discovered a new pathway that plays a part in schizophrenia," said senior author Dr. Illana Gozes, professor of neurosciences 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. It is all about balance. 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."

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Tel Aviv University