Disrupted-in-schizophrenia 1 (DISC1) protein aggregates in cerebrospinal fluid are elevated in first-episode psychosis patients

Abstract

The Disrupted-in-schizophrenia 1 (DISC1) protein is a key regulator at the intersection of signaling pathways relevant for adaptive behavior. It is prone to posttranslational changes such as misassembly and aggregation but the significance of such transformations for human mental illness has remained unclear. Here we demonstrate that DISC1 protein aggregates are increased in CSF samples of patients with first episode psychosis (n=50) compared to healthy controls (n=47), as measured by the highly sensitive surface-based fluorescence intensity distribution analysis technology that enables single aggregate detection. The concentration was in the low femtomolar range. No correlations were found to symptom levels, but the difference was particularly significant in the subset of patients receiving the diagnoses schizophrenia, unspecified (DSM IV 295.9) or schizoaffective disorder (DSM IV 295.70) at 18-month follow-up. The occurrence of protein aggregates in vivo in patients with psychotic disorders has not been previously reported. It underscores the significance of posttranslational modifications of proteins both as pathogenetic mechanisms and as potential diagnostic markers in these disorders.