Increased protein insolubility found at autopsy in brains from a subset of patients with schizophrenia may be related to the pathogenesis of the disease, according to a study published in the American Journal of Psychiatry.

Investigators conducted a pilot study examining the prefrontal cortex in autopsy brains from the Harvard Brain Tissue Resource Center (5 from patients with schizophrenia, 4 from healthy controls); a full scale study of the superior temporal gyrus in autopsy brains from the University of Pittsburgh Brain Bank (19 brains from patients with schizophrenia, 19 control); and a replication study of the prefrontal cortex in autopsy brains from University of Texas Southwestern Medical Center (18 from patients with schizophrenia, 18 control). They used cold sarkosyl fractionation to separate proteins into soluble and insoluble fractions and measured protein insolubility and ubiquitin levels for each insoluble fraction.

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Mass spectrometry analysis revealed that brains with increased insolubility and ubiquitination showed a similar peptide expression. Gene ontology enrichment analysis and ingenuity pathway analysis showed that altered proteins in the insoluble fraction were enriched for pathways relating to axon target recognition and nervous system development and function.

When examining exposure to antipsychotics, antidepressants, or benzodiazepines, there was no significant difference between brains with and without increased protein insolubility or ubiquitination. In the full-scale study, exposure to anticonvulsants was significantly associated with increased protein insolubility and ubiquitination, but this was not the case in the replication study. When samples from all studies were combined, there was no overall significant difference in anticonvulsant exposure.

“These data suggest that protein insolubility is intrinsic to the mechanism of a subset of mental illness and is not related to medication effects,” investigators wrote.

All 3 studies were limited by a small sample size.

“Determining the molecular mechanism of this subtype of schizophrenia could lead to a better understanding of the pathways underlying the clinical phenotype in some patients with major mental illness as well as to improved nosology and identification of novel therapeutic targets,” they concluded.

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Reference

Nucifora LG, MacDonald ML, Lee BJ, et al. Increased protein insolubility in brains from a subset of patients with schizophrenia [published online May 6, 2019]. Am J Psychiatry. doi:10.1176/appi.ajp.2019.18070864