Altered gene transcription linked to astrocytes and oligodendrocytes in frontal cortex in Creutzfeldt-Jakob disease

Abstract

Targeted expression of genes coding for proteins specific to astrocytes, oligodendrocytes and myelin was performed in frontal cortex area 8 of Creutzfeldt-Jakob disease methionine/methionine and valine/valine (CJD MM1 and VV2, respectively) compared with controls. GFAP (glial fibrillary acidic protein) mRNA was up-regulated whereas SLC1A2 (solute carrier family 1 member 2, coding for glutamate transporter 1: GLT1), AQ4 (aquaporin 4), MPC1 (mitochondrial pyruvate carrier 1) and UCP5 (mitochondrial uncoupled protein 5) mRNAs were significantly down-regulated in CJD MM1 and CJD VV2, and GJA1 (connexin 43) in CJD VV2. OLIG1 and OLIG2 (oligodendocyte transcription factor 1 and 2, respectively), SOX10 (SRY-Box10) and oligodendroglial precursor cell (OPC) marker NG2 (neuronal/glial antigen) 2 were preserved, but GALC (coding for galactosylceramidase), SLC2A1 (solute carrier family 2 member 1: glucose transporter member 1: GLUT1) and MCT1 (monocarboxylic acid transporter 1) mRNA expression levels were significantly reduced in CJD MM1 and CJD VV2. Expression levels of most genes linked to myelin were not altered in the cerebral cortex in CJD. Immunohistochemistry to selected proteins disclosed individual variations but GFAP, Olig-2, AQ4 and GLUT1 correlated with mRNA levels, whereas GLT1 was subjected to individual variations. However, MPC1, UCP5 and MCT1 decrease was more closely related to the respective reduced neuronal immunostaining. These observations support the idea that molecular deficits linked to energy metabolism and solute transport in astrocytes and oligodendrocytes, in addition to neurons, are relevant in the pathogenesis of cortical lesions in CJD.

Keywords: Creutzfeldt-Jakob disease; astrocytes; astrogliopathy; energy metabolism; myelin; oligodendrocytes; oligodendrogliopathy; prion diseases.

Figure 1.

Expression levels, as revealed by RT-qPCR, of genes coding for specific proteins of astrocytes (a) and oligodendrocytes (b) in frontal cortex area 8 of CJD MM1 and CJD VV2 compared with expression levels in controls. Statistical analysis of the expression data between groups uses one-way analysis of variance (ANOVA) followed by Tukey post-test for GFAP, AQP4, SLC1A2, MPC1, UCP4, GJB6, GJA1, OLIG1, OLIG2, NG2, CNP, MAL, GALC, MCT1, GJB1 and GJC2. Kruskal-Wallis test followed by Dunns post-hoc test was used for ALDH1L1, MCT4, UCP5, SOX10, MYRF, MBP, PLP1, MAG, MOG, MOBP, SLC2A1 and CLDN11 (SPSS software. IBM SPSS Statistics for Windows, Version 21.0). All data are expressed as mean ± SEM. Differences between groups are considered statistically significant at * P < 0.05, ** P < 0.01, *** P < 0.001 when comparing CJD cases with controls; and set at $ P < 0.05 and $$ P < 0.01 when comparing CJD MM1 with CJD VV2.

Figure 2.

Representative images of glial fibrillary acidic protein (GFAP), Olig-2, aquaporin 4 (AQP4), solute carrier family 1, member 1 (SLC1A2: glial affinity glutamate transporter: GLT1), mitochondrial pyruvate carrier 1 (MPC1), mitochondrial uncoupling protein 5 (UCP5), solute carrier family 2 member 1 (glucose transporter 1: GLUT1) and solute carrier family 16 member 1 (monocarboxylic acid transporter 1: MCT1) immunoreactivity in the frontal cortex area 8 of controls and cases with CJD MM1. Paraffin sections processed for immunohistochemistry and slightly stained with hematoxylin, bar = 25 μm.