Shared patterns of glial transcriptional dysregulation link Huntington's disease and schizophrenia.

Autor:	Huynh NPT; Center for Translational Neuromedicine, University of Copenhagen, Faculty of Health and Medical Sciences, 2200 Copenhagen, Denmark.; Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA., Osipovitch M; Center for Translational Neuromedicine, University of Copenhagen, Faculty of Health and Medical Sciences, 2200 Copenhagen, Denmark., Foti R; Center for Translational Neuromedicine, University of Copenhagen, Faculty of Health and Medical Sciences, 2200 Copenhagen, Denmark., Bates J; Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA., Mansky B; Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA., Cano JC; Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA., Benraiss A; Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA., Zhao C; Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Lu QR; Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Goldman SA; Center for Translational Neuromedicine, University of Copenhagen, Faculty of Health and Medical Sciences, 2200 Copenhagen, Denmark.; Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 Sep 03; Vol. 147 (9), pp. 3099-3112.
DOI:	10.1093/brain/awae166
Abstrakt:	Huntington's disease and juvenile-onset schizophrenia have long been regarded as distinct disorders. However, both manifest cell-intrinsic abnormalities in glial differentiation, with resultant astrocytic dysfunction and hypomyelination. To assess whether a common mechanism might underlie the similar glial pathology of these otherwise disparate conditions, we used comparative correlation network approaches to analyse RNA-sequencing data from human glial progenitor cells (hGPCs) produced from disease-derived pluripotent stem cells. We identified gene sets preserved between Huntington's disease and schizophrenia hGPCs yet distinct from normal controls that included 174 highly connected genes in the shared disease-associated network, focusing on genes involved in synaptic signalling. These synaptic genes were largely suppressed in both schizophrenia and Huntington's disease hGPCs, and gene regulatory network analysis identified a core set of upstream regulators of this network, of which OLIG2 and TCF7L2 were prominent. Among their downstream targets, ADGRL3, a modulator of glutamatergic synapses, was notably suppressed in both schizophrenia and Huntington's disease hGPCs. Chromatin immunoprecipitation sequencing confirmed that OLIG2 and TCF7L2 each bound to the regulatory region of ADGRL3, whose expression was then rescued by lentiviral overexpression of these transcription factors. These data suggest that the disease-associated suppression of OLIG2 and TCF7L2-dependent transcription of glutamate signalling regulators may impair glial receptivity to neuronal glutamate. The consequent loss of activity-dependent mobilization of hGPCs may yield deficient oligodendrocyte production, and hence the hypomyelination noted in these disorders, as well as the disrupted astrocytic differentiation and attendant synaptic dysfunction associated with each. Together, these data highlight the importance of convergent glial molecular pathology in both the pathogenesis and phenotypic similarities of two otherwise unrelated disorders, Huntington's disease and schizophrenia. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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