Cell Type-Specific Effects of Mutant DISC1: A Proteomics Study.
Despite the recent progress in psychiatric genetics, very few studies have focused on genetic risk factors in glial cells that, compared to neurons, can manifest different molecular pathologies underlying psychiatric disorders. In order to address this issue, we studied the effects of mutant disrupted in schizophrenia 1 (DISC1), a genetic risk factor for schizophrenia, in cultured primary neurons and astrocytes using an unbiased mass spectrometry-based proteomic approach. We found that selective expression of mutant DISC1 in neurons affects a wide variety of proteins predominantly involved in neuronal development (e.g., SOX1) and vesicular transport (Rab proteins), whereas selective expression of mutant DISC1 in astrocytes produces changes in the levels of mitochondrial (GDPM), nuclear (TMM43) and cell adhesion (ECM2) proteins. The present study demonstrates that DISC1 variants can perturb distinct molecular pathways in a cell type-specific fashion to contribute to psychiatric disorders through heterogenic effects in diverse brain cells.
Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Md., USA; Preclinical College, Guangxi University of Chinese Medicine, Nanning, PR China.
Meng
M
Xia
Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK.
Jantine A C
JA
Broek
Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Md., USA.
Yan
Y
Jouroukhin
Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK.
Jeannine
J
Schoenfelder
Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Md., USA.
Sofya
S
Abazyan
Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Md., USA.
Hanna
H
Jaaro-Peled
Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Md., USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Md., USA.
Akira
A
Sawa
Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK.
Sabine
S
Bahn
Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Md., USA; Departments of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Md., USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Md., USA; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md., USA.
Mikhail
M
Pletnikov
Astrocytes; Biomarkers; DISC1; Neurons; Proteomics; Psychiatric disorders