Markers of copper transport in the cingulum bundle in schizophrenia

Imaging and postmortem studies indicate that schizophrenia subjects exhibit abnormal connectivity in several white matter tracts, including the cingulum bundle. Copper chelators given to experimental animals damage myelin and myelin-producing oligodendrocytes, and the substantia nigra of schizophrenia subjects shows lower levels of copper, copper transporters, and copper-utilizing enzymes. This study aimed to elucidate the potential role of copper homeostasis in white matter pathology in schizophrenia. Protein levels of the copper transporters ATP7A and CTR1, and dysbindin-1, an upstream modulator of copper metabolism and schizophrenia susceptibility factor, were measured using Western blot analyses of the postmortem cingulum bundle of schizophrenia subjects (n=16) and matched controls (n=13). Additionally, the patient group was subdivided by treatment status: off- (n=8) or on-medication (n=8). Relationships between proteins from the current study were correlated among themselves and markers of axonal integrity previously measured in the same cohort. Schizophrenia subjects exhibited similar protein levels to controls, with no effect of antipsychotic treatment. The dysbindin-1A/1BC relationship was positive in controls and schizophrenia subjects; however, antipsychotic treatment appeared to reverse this relationship in a statistically different manner from that of controls and unmedicated subjects. The relationships between dysbindin-1A/neurofilament heavy and ATP7A/α-tubulin were positively correlated in the schizophrenia group that was significantly different from the lack of correlation in controls. Copper transporters and dysbindin-1 appear to be more significantly affected in the grey matter of schizophrenia subjects. However, the relationships among proteins in white matter may be more substantial and dependent on treatment status.