Systems Analysis of the 22q11.2 Microdeletion Syndrome Converges on a Mitochondrial Interactome Necessary for Synapse Function and Behavior
- Avanti Gokhale1,*,
- Cortnie Hartwig1,*,
- Amanda A.H. Freeman1,2,*,
- Julia L. Bassell1,*,
- Stephanie A. Zlatic1,
- Christie Sapp Savas7,
- Trishna Vadlamudi7,
- Farida Abudulai7,
- Tyler T. Pham4,
- Amanda Crocker8,
- Erica Werner3,
- Zhexing Wen4,
- Gabriela M. Repetto9,
- Joseph A. Gogos10,
- Steven M. Claypool11,
- Jennifer K. Forsyth12,
- Carrie E. Bearden12,
- Jill Glausier13,
- David A. Lewis13,
- Nicholas T. Seyfried5,
- Jennifer Q. Kwong6, and
- Victor Faundez1
- 1Departments of Cell Biology,
- 2Center for the Study of Human Health,
- 3Radiation Oncology,
- 4Psychiatry,
- 5Biochemistry,
- 6Pediatrics, Emory University, Atlanta, Georgia, 30322,
- 7Department of Chemistry, Agnes Scott College, Decatur, Georgia 30030,
- 8Program in Neuroscience, Middlebury College, Middlebury, Vermont 05753,
- 9Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile,
- 10Departments of Neuroscience and Physiology, Columbia University, New York, New York 10032,
- 11Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,
- 12Semel Institute for Neuroscience and Human Behavior and Department of Psychology, UCLA, Los Angeles, California, 90095, and
- 13Departments of Psychiatry and Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
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Author contributions: A.G., C.H., A.A.H.F., S.A.Z., A.C., Z.W., C.E.B., D.A.L., J.Q.K., and V.F. designed research; A.G., C.H., A.A.H.F., J.L.B., S.A.Z., C.S.S., T.V., F.A., T.T.P., A.C., E.W., Z.W., G.M.R., J.K.F., C.E.B., J.G., D.A.L., N.T.S., and J.Q.K. performed research; A.G., C.H., A.A.H.F., J.L.B., S.A.Z., C.S.S., T.V., F.A., T.T.P., A.C., E.W., Z.W., G.M.R., J.K.F., C.E.B., J.G., D.A.L., J.Q.K., and V.F. analyzed data; A.G., C.H., A.A.H.F., J.L.B., S.A.Z., J.A.G., S.M.C., J.K.F., C.E.B., D.A.L., N.T.S., J.Q.K., and V.F. edited the paper; J.A.G., S.M.C., and N.T.S. contributed unpublished reagents/analytic tools; V.F. wrote the first draft of the paper; V.F. wrote the paper.
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↵*A.G., C.H., A.A.H.F., and J.L.B. contributed equally to this work.
Abstract
Neurodevelopmental disorders offer insight into synaptic mechanisms. To unbiasedly uncover these mechanisms, we studied the 22q11.2 syndrome, a recurrent copy number variant, which is the highest schizophrenia genetic risk factor. We quantified the proteomes of 22q11.2 mutant human fibroblasts from both sexes and mouse brains carrying a 22q11.2-like defect, Df(16)A+/−. Molecular ontologies defined mitochondrial compartments and pathways as some of top ranked categories. In particular, we identified perturbations in the SLC25A1-SLC25A4 mitochondrial transporter interactome as associated with the 22q11.2 genetic defect. Expression of SLC25A1-SLC25A4 interactome components was affected in neuronal cells from schizophrenia patients. Furthermore, hemideficiency of the Drosophila SLC25A1 or SLC25A4 orthologues, dSLC25A1-sea and dSLC25A4-sesB, affected synapse morphology, neurotransmission, plasticity, and sleep patterns. Our findings indicate that synapses are sensitive to partial loss of function of mitochondrial solute transporters. We propose that mitoproteomes regulate synapse development and function in normal and pathological conditions in a cell-specific manner.
SIGNIFICANCE STATEMENT We address the central question of how to comprehensively define molecular mechanisms of the most prevalent and penetrant microdeletion associated with neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. This complex mutation reduces gene dosage of ∼63 genes in humans. We describe a disruption of the mitoproteome in 22q11.2 patients and brains of a 22q11.2 mouse model. In particular, we identify a network of inner mitochondrial membrane transporters as a hub required for synapse function. Our findings suggest that mitochondrial composition and function modulate the risk of neurodevelopmental disorders, such as schizophrenia.
- Received August 2, 2018.
- Revision received January 18, 2019.
- Accepted February 15, 2019.
- Copyright © 2019 the authors
