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Randi Hernandez was science editor at BioPharm International from September 2014 to May 2017.
The body’s over-editing of synaptic interactions is recognized as a probable cause of schizophrenia in a landmark study.
Schizophrenia may be more similar to many autoimmune conditions than previously imagined, according to a new groundbreaking study published online on Jan. 27, 2016 in the journal Nature.
In the study of 64,785 people, both with and without schizophrenia, scientists found that a particular gene in chromosome 6-C4-is responsible for what is known as overactive synaptic pruning. Pruning is the elimination of synapses, a function which is triggered by the immune system. The immune system tags synaptic interactions that are recognized as incorrect with complement protein C3, thereby sending a signal to remove these interactions so that synapses continue to fire efficiently. The researchers were guided by prior research from Beth Stevens, PhD, assistant professor of neurology at Boston Children’s Hospital and Harvard, who studied the role of complement proteins in synaptic pruning in mouse models.
Lead study author Steven McCarroll, PhD, of the Stanley Center for Psychiatric Research at the Broad Institute, and his colleagues discovered that gene structure could predict gene activity in individuals with schizophrenia. People who had long versions of the C4 genes, or those who produced more copies of the gene, were more likely to develop schizophrenia. Although presence of this version of C4 (C4A) was not always indicative of disease development-there are more than 100 chromosomal sites that are already linked to genetic risk for schizophrenia-the appearance of this particular isotope of C4 increased the risk of developing schizophrenia. As Dr. McCarroll explained to BioPharm International, “If you focus on the four common alleles, the relative risk is 1.27. So that’s a 27% increase in risk per allele. A person who inherited the higher-risk allele from each parent would have about a 54% increase in risk relative to someone who inherited the lower-risk allele from each parent.”
The authors suggest the effects of overpruning occur as early as adolescence, when brain development is at an all-time high. “Normally, pruning gets rid of excess connections we no longer need, streamlining our brain for optimal performance, but too much pruning can impair mental function,” noted Thomas Lehner, PhD, director of the Office of Genomics Research Coordination of the NIH’s National Institute of Mental Health (NIMH), which co-funded the study along with the Stanley Center for Psychiatric Research at the Broad Institute and other NIH components, in an NIH press release. “It could help explain schizophrenia’s delayed age-of-onset of symptoms in late adolescence/early adulthood and shrinkage of the brain’s working tissue. Interventions that put the brakes on this pruning process-gone-awry could prove transformative.”
Typical theories about the disease origin of schizophrenia have historically focused on viruses, prior exposure to infectious agents, classical inflammation, or autoimmunity, but these theories could never really explain the late-adolescence age of disease onset, McCarroll said. “This model is different: C4 is a molecule from the immune system, but the nervous system has repurposed it for brain development.”
People with schizophrenia typically have fewer synapses, so the knowledge of unrestrained synapse editing could provide drug developers with clues to treat the underlying cause of disease. Therapeutics engineered to tame runaway C4 could be a good starting point for future treatments, the researchers suggest. These treatments could likely come in the form of immunomodulators, now that the researchers have uncovered that the origin of schizophrenia is likely the result of a normal immune function gone amiss. Presently, all treatments for schizophrenia only address disease symptoms, such as hallucinations, psychosis, and cognitive impairment.
Sources: Nature, NIH