Protein aggregation identified in olfactory neuronal cells is associated with cognitive impairments in a subset of living schizophrenia patients

Abstract

Schizophrenia is a heterogeneous disorder, and likely results from multiple pathophysiological mechanisms. Protein aggregation, resulting from disruption of protein homeostasis (proteostasis), has been implicated in many diseases, including cancer, cardiac and pulmonary diseases, muscle diseases, and neurodegenerative disorders, but is a relatively new pathophysiological hypothesis for schizophrenia. Genetic findings implicate proteostasis in schizophrenia, and individual proteins associated with the disorder may undergo aggregation. While there is some evidence of associations between genetic variants and protein aggregation, the extent to which genetic variations influence protein aggregation remains unknown. We have previously reported increased protein insolubility and increased ubiquitination of the insoluble protein fraction, two markers of protein aggregation, in human postmortem brains from a subset of patients with schizophrenia. In the present study, we investigate whether protein aggregation is observed in an independent model system, olfactory neuronal cells derived from living patients with schizophrenia, and examine the relationship between aggregation and patient clinical and cognitive status. We demonstrate that, as in postmortem brain, olfactory neurons from a subset of patients with schizophrenia exhibit protein aggregation, identified by increased protein insolubility and ubiquitination of the insoluble protein fraction, and by ubiquitin positive protein aggregates. Patients with protein aggregation exhibit more severe cognitive deficits than those without aggregation, as revealed by between-group comparisons and correlational analyses. Understanding the mechanisms of the aggregation process, the factors that differentiate individuals who develop aggregates from those who do not, and the relationship between aggregation and cell function, has important implications for the pathophysiology of schizophrenia, and may provide insight into disease heterogeneity and novel therapeutic targets.