Abstract
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.
Original language | English |
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Pages (from-to) | 13-28 |
Number of pages | 16 |
Journal | World Journal of Biological Psychiatry |
Volume | 21 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2 2020 |
Externally published | Yes |
Funding
We would like to thank the Maryland Brain Collection staff for the samples used in this study. The ICP-MS is supported by the UAB Cyclotron Facility. Additionally, this work was supported by the National Institute of Mental Health R0166123 and R21MH108867 to RCR, as well as the National Institute of Neurological Disorders and Stroke F99NS105208 to KES.
Funders | Funder number |
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UAB Cyclotron Facility | |
National Institute of Mental Health | R0166123, R21MH108867 |
National Institute of Neurological Disorders and Stroke | F99NS105208 |
Keywords
- Schizophrenia
- copper
- dysbindin
- post-mortem
- substantia nigra