Frederick Nucifora’s background in neurodegenerative disorders has made him wonder if some of the same mechanisms contributing to these diseases could also occur in schizophrenia or other mental illnesses.
Changes in stress-related cascades, including inflammatory and endocrine processes that have been linked to schizophrenia, can disrupt normal protein quality controls or modify proteins, Nucifora explains. In fact, protein insolubility has been implicated in many disorders, including cancer, cardiac and pulmonary disease, and neurodegenerative disorders. In Alzheimer’s disease, protein builds up as plaque; in Huntington’s disease, it presents as occlusions or blockages; and in Parkinson’s disease, it presents as Lewy bodies, abnormal proteins occurring in brain nerve cells.
“We hypothesized that there may be either disruption of protein quality control or misfolded proteins also occurring in schizophrenia,” says Nucifora.
His team studied autopsied brains from 19 patients with schizophrenia and 19 healthy controls. Separating out the brain’s proteins through a process called fractionation, the researchers measured levels of total and insoluble protein. They observed an increase in the amount of insoluble protein in a subset of patients with schizophrenia. The investigators then studied the samples looking for ubiquitin, a known marker for protein insolubility in neurodegenerative disorders and a signal for protein insolubility, according to Nucifora’s prior research. They saw an increase in ubiquitination, the bonding of ubiquitin to proteins in the same subset of schizophrenia patients who had more insoluble protein.
“What’s interesting is this provides novel insight that protein insolubility can be a pathological mechanism leading to schizophrenia, at least in a subset of patients,” Nucifora says. Schizophrenia is thought to be a diverse disease, he adds, so it makes sense that this mechanism would be found in just some patients. Because the samples were from autopsy brains, his team didn’t have enough information to link the finding to patients with any particular clinical presentation. Understanding the molecular mechanism of this subtype of schizophrenia could lead to a better understanding of the pathways, circuitry and behavioral symptoms seen in patients with mental illness.
“This could cut across diagnoses,” he says, perhaps also occurring in bipolar disorder or major depressive disorder. “If we understand that, we could try to develop therapeutic targets that could be directed at this process.”
Ultimately, Nucifora would like to study this in additional cases. Meanwhile, follow-up studies planned in olfactory neurons—nerve cells taken from the system regulating sense of smell—will test different stressors to see which ones may contribute to protein insolubility and the development of schizophrenia.