MicroRNA-21: Expression in oligodendrocytes and correlation with low myelin mRNAs in depression and alcoholism

Abstract

MiR-21 is a microRNA implicated in cancer, development, and cardiovascular diseases and expressed in the central nervous system (CNS), especially after injury. However, the cellular expression of miR-21 in the adult CNS has not been clearly established either in mice or human subjects, while its alteration in psychiatric disorders is unknown. MiR-21 expression was characterized in reporter mice expressing β–galactosidase (LacZ) under the endogenous miR-21 promoter (miR-21/LacZ). Brain co-localization of miR-21/LacZ with specific neural markers was examined by double immunofluorescence in reporter mice, while extent of immunostaining for myelin basic protein and PDGFRα was determined in miR-21 knockout and wild-type mice. Levels of miR-21, and mRNAs of selected miR-21 targets, miR-21 regulator STAT3 and myelin-related proteins were measured by qRT-PCR in the white matter (WM) adjacent to the left postmortem orbitofrontal cortex (OFC) of human subjects with major depressive disorder (MDD), alcoholism, comorbid MDD plus alcoholism (MDA) and non-psychiatric control subjects. MiR-21/LacZ was highly expressed in cell bodies of WM and myelinated portions of gray matter (GM). Labeled cell bodies were identified as oligodendrocytes, while miR-21/LacZ was barely detectable in other cell types. MiR-21, as well as the mRNAs of several myelin-related proteins, were reduced in the WM of subjects with MDD and alcoholism. MiR-21 positively correlated with mRNA of myelin-related proteins and astrocytic GFAP. High expression of miR-21 in adult oligodendrocytes and the correlation of miR-21 decrease with mRNA of some myelin proteins, regulator STAT3, and oligodendrocyte-related transcription factors suggest an involvement of miR-21 in WM alterations in depression and alcoholism.

Molecular Neuropathology of Astrocytes and Oligodendrocytes in Alcohol Use Disorders

“…These reductions are particularly significant in chronic alcoholics with cirrhosis as compared to non-alcoholic controls or to non-cirrhotic alcoholics (Lewohl et al, 2005 ), suggesting that nutritional deficiencies or metabolic toxicity, possibly interacting with direct ethanol effects, strongly deplete the expression of myelin components in alcoholics, at least as assessed in studies that include GM in the probed tissue. In contrast, in a recent study from our laboratory, we used samples only from the WM adjacent to cortical area 47 (orbitofrontal cortex) in chronic alcoholics, and observed that mRNA levels for myelin proteins PLP, MAG and MOG and other oligodendrocyte markers were markedly lower than in controls, although the levels of MBP mRNA were not changed (Miguel-Hidalgo et al, 2017 ). Since cirrhosis had not been diagnosed in most subjects of our study, these results suggest that the effects of prolonged alcohol abuse in some regions of WM may occur without cirrhosis and be different from those when GM is included.…”

“…Increased miRNAs include some targeting major myelin proteins such as PLP1 and CNPase as well as transcription factor C11ORF9, a regulator of myelin formation. In our recent work, we found that miR-21, high in oligodendrocytes, was strongly and positively correlated with decreased PLP1 miRNA (which is not a direct target of miR-21; Miguel-Hidalgo et al, 2017 ). The networks and pathways regulated by differentially expressed miRNAs in human alcoholics and mice are very highly enriched in oligodendrocytes and astrocytes, some of them exclusively for each cell type (Nunez et al, 2013 ).…”

“…On the other hand, given the frequent co-abuse of ethanol and tobacco, part of the deleterious effects of ethanol on myelin proteins might result from an interaction of ethanol with specific components of tobacco, such as nicotine-specific nitrosamine ketone (NNK; Tong et al, 2015 ; Zabala et al, 2015 ; Papp-Peka et al, 2017 ). However, even in subjects without such obvious neurological and anatomical complications (the “uncomplicated cases”), the expression of myelin and oligodendrocyte-related proteins, or their mRNAs, can be significantly altered in various brain regions, being particularly prominent in the PFC (Mayfield et al, 2002 ; Alexander-Kaufman et al, 2006 ; Liu et al, 2006 ), which are reflected in low levels of the main structural myelin proteins such as myelin basic protein (MBP) and possibly proteolipid protein (PLP), their companions, myelin associated-glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (Omgp; Okamoto et al, 2006 ), and related transcription factors (Miguel-Hidalgo et al, 2017 ). Reduced expression of major myelin proteins such as MBP has been detected in models of prenatal alcohol exposure (Ozer et al, 2000 ; Bichenkov and Ellingson, 2001 ), while in vitro studies have shown that the effects of ethanol on the expression of myelin components could be mediated by direct regulation of PKC-like enzymes rather than by altering their expression (Bichenkov and Ellingson, 2002 ).…”

“…Studies have also shown significant increases of PFC miRNAs in subjects with AUDs (Lewohl et al, 2011 ), although in WM some miRNAs would be decreased (Miguel-Hidalgo et al, 2017 ). Increased miRNAs include some targeting major myelin proteins such as PLP1 and CNPase as well as transcription factor C11ORF9, a regulator of myelin formation.…”

Transcriptomics Evidence for Common Pathways in Human Major Depressive Disorder and Glioblastoma

“…Most of these miRNAs are contained in common miRNAs. For example, Hsa-miR-21 is not only involved in the alterations of white matter in depression and alcoholism [ 26 ], but it also plays a key role in the pathogenesis of GBM and can be used as a biomarker for the diagnosis and treatment of GBM patients [ 27 ]. The miRNAs were found to be closely related to the abnormal expression of CD3, CD14, CD19, and CD56 in immune cells category.…”