Isoform and protein region abnormalities of dysbindin and copper transporter proteins in postmortem schizophrenia substantia nigra

Abstract

AbstractObjectiveDysbindin is downregulated in several schizophrenia brain regions and modulates copper transport required for myelination and monoamine metabolism. We sought to determine dysbindin and copper transporter protein expression in schizophrenia subjects.MethodsWe studied the substantia nigra (which exhibits one of the highest copper contents of the human brain) using Western blot analysis. We characterized specific protein domains of copper transporters ATP7A, CTR1, ATP7B, and dysbindin isoforms 1A and 1B/C in postmortem substantia nigra in schizophrenia subjects (n=15) and matched controls (n=11). As a preliminary investigation, we examined medication status in medicated (n=11) versus unmedicated schizophrenia subjects (n=4).ResultsThe combined schizophrenia group exhibited increased levels of C-terminus, but not N-terminus, ATP7A. Schizophrenia subjects expressed less transmembrane CTR1 and dysbindin 1B/C than controls. When subdivided, the increased C-terminus ATP7A protein was present only in medicated subjects versus controls. Unmedicated subjects exhibited less N-terminus ATP7A protein than controls and medicated subjects, suggesting medication-induced rescue of the ATP7A N-terminus. Transmembrane CTR1 was decreased to a similar extent in both treatment groups versus controls, suggesting no medication effect.ConclusionsThese results provide the first evidence of disrupted copper transport into and within schizophrenia nigral cells that may be modulated by specific dysbindin isoforms and antipsychotic treatment.