Elevated ubiquitinated proteins in brain and blood of individuals with schizophrenia

Abstract

Dysregulation of the ubiquitin proteasome system (UPS) has been linked to schizophrenia but it is not clear if this dysregulation is detectable in both brain and blood. We examined free mono-ubiquitin, ubiquitinated proteins, catalytic ubiquitination, and proteasome activities in frozen postmortem OFC tissue from 76 (38 schizophrenia, 38 control) matched individuals, as well as erythrocytes from 181 living participants, who comprised 30 individuals with recent onset schizophrenia (mean illness duration = 1 year), 63 individuals with ‘treatment-resistant’ schizophrenia (mean illness duration = 17 years), and 88 age-matched participants without major psychiatric illness. Ubiquitinated protein levels were elevated in postmortem OFC in schizophrenia compared to controls (p = <0.001, AUC = 74.2%). Similarly, individuals with ‘treatment-resistant’ schizophrenia had higher levels of ubiquitinated proteins in erythrocytes compared to those with recent onset schizophrenia (p < 0.001, AUC = 65.5%) and controls (p < 0.001, AUC = 69.4%). The results could not be better explained by changes in proteasome activity, demographic, medication, or tissue factors. Our results suggest that 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. A derangement in protein ubiquitination may be linked to pathogenesis or neurotoxicity in schizophrenia, and its manifestation in the blood may have prognostic utility.

Comprehensive gene expression analysis detects global reduction of proteasome subunits in schizophrenia

“…This finding was replicated in 8 independent datasets of 5 different brain regions of overall 267 schizophrenia and 266 control samples, in both elderly and relatively young patients. A plausible scenario that stems from our results is that the observed down-regulation causes reduced proteasomal activity, which leads to the recently detected aggregation of ubiquitinated proteins in schizophrenia (10,12).…”

“…suggesting that the aggregation of ubiquitinated proteins is related to disease pathogenesis, possibly through disruption of relevant pathways. While decreased proteasome activity is generally associated with ubiquitinated protein accumulation (13), recent efforts to explore interruption of proteasome activity in schizophrenia led to inconsistent results (10,11).…”

“…Ubiquitinated protein levels were found to be elevated in the orbitofrontal cortex of patients with schizophrenia compared to controls (10). Similarly, individuals with treatment-resistant schizophrenia had higher levels of ubiquitinated proteins in erythrocytes compared to those with recent disease onset (10). Searching for a possible mechanism, no change has been detected in (10) in proteasome activity between schizophrenia and control, in neither blood nor brain.…”

“…Recent findings suggest a more pronounced role of the UPS in the pathogenesis of schizophrenia. Ubiquitinated protein levels were found to be elevated in the orbitofrontal cortex of patients with schizophrenia compared to controls (10). Similarly, individuals with treatment-resistant schizophrenia had higher levels of ubiquitinated proteins in erythrocytes compared to those with recent disease onset (10).…”

“…Similarly, individuals with treatment-resistant schizophrenia had higher levels of ubiquitinated proteins in erythrocytes compared to those with recent disease onset (10). Searching for a possible mechanism, no change has been detected in (10) in proteasome activity between schizophrenia and control, in neither blood nor brain. Another study (11), however, did find intra-cellular compartment-specific dysfunction of the proteasome activity in STG samples patients with schizophrenia from the Mount Sinai School of Medicine (MSSM) cohort.…”