Impaired copper transport in schizophrenia results in a copper-deficient brain state: A new side to the dysbindin story

Abstract

<b>Objectives:</b> Several schizophrenia brain regions exhibit decreased dysbindin. Dysbindin modulates copper transport crucial for myelination, monoamine metabolism and cellular homeostasis. Schizophrenia patients (SZP) exhibit increased plasma copper, while copper-decreasing agents produce schizophrenia-like behavioural and pathological abnormalities. Therefore, we sought to determine dysbindin and copper transporter protein expression and copper content in SZP.<b>Methods:</b> We studied the copper-rich substantia nigra (SN) using Western blot and inductively-coupled plasma mass spectrometry. We characterised specific protein domains of copper transporters ATP7A, CTR1, ATP7B and dysbindin isoforms 1 A and 1B/C in SZP (<i>n</i> = 15) and matched controls (<i>n</i> = 11), and SN copper content in SZP (<i>n</i> = 14) and matched controls (<i>n</i> = 11). As a preliminary investigation, we compared medicated (ON; <i>n</i> = 11) versus unmedicated SZP (OFF; <i>n</i> = 4).<b>Results:</b> SZP exhibited increased C terminus, but not N terminus, ATP7A. SZP expressed less transmembrane CTR1 and dysbindin 1B/C than controls. ON exhibited increased C terminus ATP7A protein versus controls. OFF exhibited less N terminus ATP7A protein than controls and ON, suggesting medication-induced rescue of the ATP7A N terminus. SZP exhibited less SN copper content than controls.<b>Conclusions:</b> These results provide the first evidence of disrupted copper transport in schizophrenia SN that appears to result in a copper-deficient state. Furthermore, copper homeostasis may be modulated by specific dysbindin isoforms and antipsychotic treatment.