Unbiased Metabolite Profiling of Schizophrenia Fibroblasts under Stressful Perturbations Reveals Dysregulation of Plasmalogens and Phosphatidylcholines.
We undertook an unbiased metabolite profiling of fibroblasts from schizophrenia patients and healthy controls to identify metabolites and pathways that are dysregulated in disease, seeking to gain new insights into the disease biology of schizophrenia and to discover potential disease-related biomarkers. We measured polar and nonpolar metabolites in the fibroblasts under normal conditions and under two stressful physiological perturbations: growth in low-glucose media and exposure to the steroid hormone dexamethasone. We found that metabolites that were significantly different between schizophrenia and control subjects showed separation of the two groups by partial least-squares discriminant analysis methods. This separation between schizophrenia and healthy controls was more robust with metabolites identified under the perturbation conditions. The most significant individual metabolite differences were also found in the perturbation experiments. Metabolites that were significantly different between schizophrenia and healthy controls included a number of plasmalogens and phosphatidylcholines. We present these results in the context of previous reports of metabolic profiling of brain tissue and plasma in schizophrenia. These results show the applicability of metabolite profiling under stressful perturbations to reveal cellular pathways that may be involved in disease biology.
Center for Experimental Drugs and Diagnostics, Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Harvard Medical School and Massachusetts General Hospital , Boston, Massachusetts 02114, United States.|Chemical Biology Program, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
Joanne H
JH
Huang
Institute of Neuroinformatics, ETH Zurich and University of Zurich , CH-8057, Zurich, Switzerland.
Hyoungjun
H
Park
Center for Experimental Drugs and Diagnostics, Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Harvard Medical School and Massachusetts General Hospital , Boston, Massachusetts 02114, United States.|Chemical Biology Program, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
Jonathan
J
Iaconelli
Center for Experimental Drugs and Diagnostics, Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Harvard Medical School and Massachusetts General Hospital , Boston, Massachusetts 02114, United States.|Chemical Biology Program, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
Shaunna S
SS
Berkovitch
Center for Experimental Drugs and Diagnostics, Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Harvard Medical School and Massachusetts General Hospital , Boston, Massachusetts 02114, United States.|Chemical Biology Program, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
Bradley
B
Watmuff
Schizophrenia and Bipolar Disorder Program, Harvard Medical School and McLean Hospital , Belmont, Massachusetts 02478, United States.
Donna
D
McPhie
Schizophrenia and Bipolar Disorder Program, Harvard Medical School and McLean Hospital , Belmont, Massachusetts 02478, United States.
Dost
D
Öngür
Schizophrenia and Bipolar Disorder Program, Harvard Medical School and McLean Hospital , Belmont, Massachusetts 02478, United States.
Bruce M
BM
Cohen
Chemical Biology Program, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
Clary B
CB
Clish
Center for Experimental Drugs and Diagnostics, Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Harvard Medical School and Massachusetts General Hospital , Boston, Massachusetts 02114, United States.|Chemical Biology Program, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.|Schizophrenia and Bipolar Disorder Program, Harvard Medical School and McLean Hospital , Belmont, Massachusetts 02478, United States.
Rakesh
R
Karmacharya
D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D003470:Culture Media / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D016002:Discriminant Analysis; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005938:Glucocorticoids / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency / Q000494:pharmacology; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D055442:Metabolome; D008875:Middle Aged; D010713:Phosphatidylcholines / Q000378:metabolism*; D010955:Plasmalogens / Q000378:metabolism*; D061251:Primary Cell Culture; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013312:Stress, Physiological
D014150:Antipsychotic Agents; D015415:Biomarkers; D003470:Culture Media; D005938:Glucocorticoids; D010713:Phosphatidylcholines; D010955:Plasmalogens; D003907:Dexamethasone; D005947:Glucose
metabolic profiling; phosphatidylcholine; plasmalogen; schizophrenia