Alterations in oligodendrocyte transcriptional networks reveal region-specific vulnerabilities to neurological disease

• Published in: iScience Vol. 26; no. 4; p. 106358
• Main Authors: Tommasini, Dario, Fox, Rachel, Ngo, Kathie J., Hinman, Jason D., Fogel, Brent L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.04.2023; Elsevier
• Subjects: Biological sciences; Cellular neuroscience; Neuroscience; Cellular neuroscience; Neuroscience; Biological sciences
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.106358

Neurological disease is characterized by the dysfunction of specific neuroanatomical regions. To determine whether region-specific vulnerabilities have a transcriptional basis at cell-type-specific resolution, we analyzed gene expression in mouse oligodendrocytes across various brain regions. Oligodendrocyte transcriptomes cluster in an anatomical arrangement along the rostrocaudal axis. Moreover, regional oligodendrocyte populations preferentially regulate genes implicated in diseases that target their region of origin. Systems-level analyses identify five region-specific co-expression networks representing distinct molecular pathways in oligodendrocytes. The cortical network exhibits alterations in mouse models of intellectual disability and epilepsy, the cerebellar network in ataxia, and the spinal network in multiple sclerosis. Bioinformatic analyses reveal potential molecular regulators of these networks, which were confirmed to modulate network expression in vitro in human oligodendroglioma cells, including reversal of the disease-associated transcriptional effects of a pathogenic Spinocerebellar ataxia type 1 allele. These findings identify targetable region-specific vulnerabilities to neurological disease mediated by oligodendrocytes. [Display omitted] •Mouse oligodendrocyte (OL) genes are expressed in a rostrocaudal gradient in the brain•Regional OL gene networks are altered in diseases affecting corresponding regions•Candidate regulators of OL gene networks modulate expression in vitro in human cells•Model: Targetable regional vulnerability to neurological disease is mediated by OLs Biological sciences; Neuroscience; Cellular neuroscience