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

• DOI: 10.1093/brain/awae166
• Publication Date: 2024-07-19T16:44:25Z
• Authors: Nguyen P T Huynh; Mikhail Osipovitch; Rossana Foti; Janna Bates; Benjamin Mansky; Jose C Cano; Abdellatif Benraiss; Chuntao Zhao; Q Richard Lu; Steven A Goldman
• Keywords: schizophrenia; 0301 basic medicine; 03 medical and health sciences; astrocyte; synapse; glial progenitor cell; Huntington disease; neurogenetics; oligodendrocyte

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 hypomyelination. To assess whether a common mechanism might underlie the similar pathology of these otherwise disparate conditions, we used comparative correlation network approaches to analyse RNA-sequencing data from human progenitor cells (hGPCs) produced disease-derived pluripotent stem cells. We identified gene sets preserved between hGPCs yet normal controls that included 174 highly connected genes shared disease-associated network, focusing on involved synaptic signalling. These were largely suppressed hGPCs, regulatory analysis core set upstream regulators this which OLIG2 TCF7L2 prominent. Among their downstream targets, ADGRL3, modulator glutamatergic synapses, was notably hGPCs. Chromatin immunoprecipitation sequencing confirmed each bound region whose expression then rescued by lentiviral overexpression transcription factors. suggest suppression TCF7L2-dependent glutamate signalling may impair receptivity neuronal glutamate. The consequent loss activity-dependent mobilization yield deficient oligodendrocyte production, hence hypomyelination noted disorders, well disrupted differentiation attendant associated each. Together, highlight importance convergent molecular pathogenesis phenotypic similarities two unrelated schizophrenia.