Ubiquitinated Proteins Higher in Schizophrenia and Increase With Severity

blood test_TS
blood test_TS
Investigators examined brain tissue and blood from patients with schizophrenia and through a global polyubiquitination assay found ubiquitination was lower in the erythrocytes of patients with treatment-resistant schizophrenia.

Levels of ubiquitinated proteins in both brain and erythrocytes are elevated in patients with schizophrenia and continue to increase as the disease process continues, according to a study published in Scientific Reports.

Researchers analyzed the levels of the ubiquitin-proteasome system in both the orbitofrontal cortex and erythrocytes in patients with schizophrenia to determine if levels could be used to serve as a marker for disease stages. Postmortem samples of orbitofrontal cortex were obtained from 38 patients with schizophrenia and 38 healthy controls and blood erythrocyte samples were taken from 63 patients with treatment-resistant schizophrenia, 30 patients with recent onset schizophrenia, and 88 healthy controls.

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Clinical measurements included a diagnosis based on the Structured Clinical Interview for DSM-IV Axis I Disorders or the Mini International Neuropsychiatric Interviews and symptom severity was measured using the Scale for the Assessment of Negative Symptoms, the Expanded Brief Psychiatric Rating Scale, and/or the Positive and Negative Syndrome Scale. Levels of free mono-ubiquitin, ubiquitinated proteins, catalytic ubiquitination, and proteasome activity comprised the ubiquitin-proteasome system measurements.

In patients with schizophrenia, ubiquitinated protein levels in the orbitofrontal cortex were 25.5% (P <.001) higher than in the healthy controls. In patients with treatment-resistant schizophrenia, ubiquitinated protein levels in erythrocytes were 33.1% (P <.001) higher than in patients with recent-onset schizophrenia and 34.5% (P <.001) higher than in healthy controls. Also, in patients with treatment-resistant schizophrenia, there was an association between increased ubiquitinated protein levels and increased general psychopathology measured on the Positive and Negative Syndrome Scale (P =.017) and negative symptom severity measured on the Scale for the Assessment of Negative Symptoms (P =.026).

Ubiquitination activity was lower in erythrocytes in patients with treatment-resistant schizophrenia when compared with healthy controls, but not in patients with recent-onset schizophrenia. Levels of free mono-ubiquitin and proteasome activity in the orbitofrontal cortex and erythrocytes remained the same for patients with schizophrenia and healthy controls.

Limitations of this study include not identifying a mechanism for the increase in ubiquitinated proteins or the impact this might have on patients with schizophrenia.

Researchers concluded, “ubiquitinated protein formation may be abnormal in both the brain and erythrocytes of those with schizophrenia, particularly in the later stages or specific sub-groups of the illness.”

One author declared affiliation with several pharmaceutical companies. Please refer to original reference for a full list of disclosures.


Bousman CA, Luza S, Mancuso SG, et al. Elevated ubiquitinated proteins in brain and blood of individuals with schizophrenia. Sci Rep. 2019;9(1):2307.