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

World J Biol Psychiatry. 2020 Jan;21(1):13-28. doi: 10.1080/15622975.2018.1523562. Epub 2018 Dec 20.


Objectives: 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.Methods: 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 (n = 15) and matched controls (n = 11), and SN copper content in SZP (n = 14) and matched controls (n = 11). As a preliminary investigation, we compared medicated (ON; n = 11) versus unmedicated SZP (OFF; n = 4).Results: 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.Conclusions: 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.

Keywords: Schizophrenia; copper; dysbindin; post-mortem; substantia nigra.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / pathology*
  • Case-Control Studies
  • Copper / deficiency
  • Copper / metabolism*
  • Copper Transporter 1 / metabolism*
  • Copper-Transporting ATPases / metabolism*
  • Dysbindin / metabolism*
  • Humans
  • Mass Spectrometry
  • Schizophrenia / genetics*
  • Substantia Nigra / metabolism


  • Copper Transporter 1
  • DTNBP1 protein, human
  • Dysbindin
  • SLC31A1 protein, human
  • Copper
  • ATP7A protein, human
  • Copper-Transporting ATPases