Fig. 8: An HD rat model mimics the BDNF decrease and GSTO2 increase preceding TH elevation.
a–d, Representative western blots and box plots (boxes show mean and central quartiles; whiskers show data range) from the rat model SPRDtgHD striatal tissues analysis, n = 5 per group (two females and three males) show significantly decreased BDNF, **P = 0.008 (a); and increased GSTO2 protein levels, *P = 0.01 (b), while TH is still unchanged P = 0.33 (c) and TrkB levels are similar to controls, P = 0.32 (d). e, Cartoon illustrating the events leading to GSTO2 upregulation by mHTT and its consequences. f, Bar plot comparison of gene expression changes in the pre-frontal cortex Brodmann Area 9 (BA9) and the caudate nucleus (CAU) of patients asymptomatic for HD+ and control individuals show upregulation of GSTO2 in the CAU brain region of HD+ (adj P = 1.53 × 10−15; red arrow) compared to the non-significant difference in controls (ns, adj P = 0.99). GSTO1 is significantly downregulated (blue arrow, adj P = 8.67 × 10−8) in asymptomatic HD+, while non-significantly different (adj p = 0.99) in controls. g, Bar plot, similar to our results, in patients with grade 2–4 HD, RNA-seq analysis of iSPNs revealed downregulation of GSTO2 (blue arrow, P = 3.06 × 10−6). h, Bar plot showing differential gene expression of some marker genes (as per Fig. 3f) involved in glutathione metabolism (log2(fold change) CAU/BA9 of asymptomatic HD+ and control brains). Genes indicated with a red arrow were significantly upregulated in asymptomatic HD+ (GCLC, adj P = 3.55 × 10−21; GSTM2 adj P = 1.52 × 10−37) but not significantly different (ns) in controls apart from GSTM2 adj P = 0.02, whereas genes indicated with a blue arrow were significantly downregulated in asymptomatic HD+ (GPX1, adj P = 0.01; GSR, adj P = 0.01; GSS, adj P = 1.72 × 10−5; GGT7, adj P = 1.67 × 10−17). No significant changes were observed in the controls. i, Bar plot showing differential gene expression of some marker genes (as per Fig. 3f) involved in glutathione metabolism, mostly downregulated or not significantly different in patients with grade 2–4 HD. Values are expressed as log(fold change) control of patients with grade -2–4 HD in iSPN (ABCC1, P = 6.30 × 10−5; GSS, P = 0.0007; GCLC, P = 9.86 × 10−5; GSTM2, P = 0.036; GGT7, P = 1.49 × 10−8); in direct pathway SPN (dSPN) (GSS, P = 0.04; GCLC, P = 1.55 × 10−6; GSTM2, P = 0.02; GGT7, P = 0.0001). Data in f and h were extracted from a previous publication (additional file 5 (T-test (3) vs (5))47; they are from two asymptomatic patients with HD+ and two appropriate control brains. Data in g and i were extracted from a different publication (Table S2)48. Values are means; error bars, s.e.m. P statistic in a–d from unpaired, two-tailed Student’s t-test. Box plot statistics for a–d are reported in the figure source data. This figure was partially created with BioRender.com (two neurons in e).
