MiR-142-3p regulates cortical oligodendrocyte gene co-expression networks associated with tauopathy

Jason D. Hinman*, Kathie J. Ngo, Deborah Kim, Cidi Chen, Carmela R. Abraham, Mohsen Ghanbari, M. Arfan Ikram, Steven A. Kushner, Riki Kawaguchi, Giovanni Coppola, Kerstin Goth, Saverio Bellusci, Israel Hernandez, Kenneth S. Kosik, Brent L. Fogel

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

Oligodendrocytes exist in a heterogenous state and are implicated in multiple neuropsychiatric diseases including dementia. Cortical oligodendrocytes are a glial population uniquely positioned to play a key role in neurodegeneration by synchronizing circuit connectivity but molecular pathways specific to this role are lacking. We utilized oligodendrocyte-specific translating ribosome affinity purification and RNA-seq (TRAP-seq) to transcriptionally profile adult mature oligodendrocytes from different regions of the central nervous system. Weighted gene co-expression network analysis reveals distinct region-specific gene networks. Two of these mature myelinating oligodendrocyte gene networks uniquely define cortical oligodendrocytes and differentially regulate cortical myelination (M8) and synaptic signaling (M4). These two cortical oligodendrocyte gene networks are enriched for genes associated with dementia including MAPT and include multiple gene targets of the regulatory microRNA, miR-142-3p. Using a combination of TRAP-qPCR, miR-142-3p overexpression in vitro, and miR-142-null mice, we show that miR-142-3p negatively regulates cortical myelination. In rTg4510 tau-overexpressing mice, cortical myelination is compromised, and tau-mediated neurodegeneration is associated with gene co-expression networks that recapitulate both the M8 and M4 cortical oligodendrocyte gene networks identified from normal cortex. We further demonstrate overlapping gene networks in mature oligodendrocytes present in normal cortex, rTg4510 and miR-142-null mice, and existing datasets from human tauopathies to provide evidence for a critical role of miR-142-3p-regulated cortical myelination and oligodendrocyte-mediated synaptic signaling in neurodegeneration.

Original languageEnglish
Pages (from-to)103-118
Number of pages16
JournalHuman Molecular Genetics
Volume30
Issue number1
DOIs
Publication statusPublished - 1 Jan 2021

Bibliographical note

Funding:
National Multiple Sclerosis Society (PP1892 to J.D.H.); the National Institute for Neurological Disorders and Stroke (R01 NS082094 to B.L.F.); the National Institute for Neurological Disorders and Stroke (K08 NS083740 to J.D.H.); the Deutsche Forschungsgemeinschaft (BE4443/4-1, BE4443/6-1, CRC1213 to S.B.); Landes-Offensive zur Entwicklung Wissenschaftlichökonomischer Exzellenz (to S.B.); the Universtätsklinikum Giessen Marburg, the University of Giessen Marburg Lung Center, the German Center for Lung Research (DZL to S.B.); COST (BM1201 to S.B.); the Program of Competitive Growth of Kazan Federal University (to S.B.). Additional support was provided by the United States Department of Veterans Affairs Greater Los Angeles Healthcare System and the UCLA Department of Neurology.

Publisher Copyright: © 2020 The Author(s) 2020. Published by Oxford University Press. All rights reserved.

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