Protein Buildup in the Brain a New Target for Schizophrenia?

Megan Brooks

July 03, 2019

Protein buildup in the brain, similar to that seen in the brains of patients with Alzheimer disease and Parkinson disease, may be a pathologic mechanism for some cases of schizophrenia. The finding could lead to the development of novel treatments for the disorder, new research suggests.

"Researchers have been so focused on the genetics of schizophrenia that they've not paid as much attention to what is going on at the protein level and especially the possibility of protein aggregation. This may be a whole new way to look at the disorder and develop more effective therapies," lead investigator Frederick Nucifora Jr, PhD, assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine in Baltimore, Maryland, said in a news release.

The study was published online May 6 in the American Journal of Psychiatry.

A New Concept

The investigators studied 42 postmortem brain tissue samples from persons who had had schizophrenia and a comparison set of postmortem samples from 41 brains that had no abnormalities and that served as controls.

Twenty of the schizophrenia brains showed an increase in protein insolubility as well as elevated levels of ubiquitin, a marker of protein aggregation in neurodegenerative disorders. These changes were absent in the normal brain tissue samples.

Animal studies indicate that treatment with antipsychotics does not cause the accumulation of undissolvable proteins or ubiquitin, suggesting that the disease itself, not these medications, caused abnormal protein buildup in some of the brains of persons who had had schizophrenia, the researchers note.

Results of mass spectroscopy suggest that many of the abnormal proteins are involved in nervous system development and function — specifically in generating new neurons and the connections through which neurons communicate with one another. This is consistent with theories of schizophrenia that trace its origins to brain development and to problems with neural communication.

"This is a relatively new concept to the field of schizophrenia," Nucifora told Medscape Medical News.

"This is the first report that looks at general markers of protein insolubility/aggregation in sporadic cases of schizophrenia. At this time, there is no way to know how prevalent this process is. It occurred in about 50% of the brains from patients with schizophrenia that we looked at," he said.

Implications for Other Disorders?

Nucifora added that the findings suggest a novel way to classify schizophrenia, and potentially other mental illnesses, at the pathologic level.

"For example, there may be a subset of patients with BPAD [bipolar affective disorder] that have this process occurring also, and they would be classified with this subpopulation of patients with schizophrenia, since they have a common pathological mechanism," he explained.

The findings may also provide insight into the clinical manifestations of schizophrenia.

"For example, this subset of patients may be more likely to have certain symptoms related to schizophrenia (ie, negative symptoms or cognitive deficits or have a more chronic course or be treatment refractory). This could also provide novel therapeutic targets and potentially precision psychiatry related to the subset of patients with this process," said Nucifora.

Commenting on the findings for Medscape Medical News, Scott Krakower, DO, assistant unit chief of psychiatry, Zucker Hillside Hospital, Glen Oaks, New York, said the findings were interesting and "definitely worth exploring further."

Krakower noted that other studies have shown changes in protein biosynthesis in cases of dementia and chronic traumatic encephalopathy, "so it's not far off to think that there could be changes in protein synthesis and buildup of proteins in schizophrenia. Over time, we may be able to find certain agents that may help to dissolve these types of proteins that buildup," Krakower said.

The research was supported by the Brain and Behavior Research Foundation Young Investigator Awards. Nucifora and Krakower have disclosed no relevant financial relationships.

Am J Psychiatry. Published online May 6, 2019. Abstract

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