Fig. 3: Transcriptional changes induced by Trkb deletion in iSPN.

a–c, Volcano plots summarizing the RNA-seq data results. DEGs between iSPN⁺mut and control at 3 months (a) and 8 months (b) and from the comparison between iSPN⁺mut 3 months vs 8 months (c). Brown and blue dots indicate genes with significantly increased or decreased expression, respectively. Genes with log₁₀(adj P value) > 4 are indicated in a–c. d, Venn diagram representing unique and common genes differentially expressed in iSPN⁺ population comparison sets. e, Comparison of RPKM values between iSPN⁺mut populations and the respective counterpart (iSPN⁻mut populations) for the 34 overlapping genes from the Venn diagram in d. At 8 months, comparing iSPN⁺mut and iSPN^-mut populations (n = 6 biological replicas per population type), Cbr3 was specifically downregulated in iSPN⁺mut vs iSPN⁻mut (P = 0.03). At 3 months, iSPN⁺mut populations (n = 4 biological replicas) and iSPN⁻mut populations (n = 5 biological replicas), four genes (Gcc1, P = 0.01; Atxn7l3, P = 0.0009; Zfp101, P = 0.03, and BC048403, P = 0.02) were specifically downregulated whereas Gsto2 (P = 0.008) was specifically upregulated in iSPN⁺mut vs iSPN⁻mut. RPKM, reads per kilobase of transcript per million reads mapped. f, Plot showing some DEGs (DESeq2) involved in the glutathione metabolism (log₂(fold change) of iSPN⁺mut/iSPN⁺wt). At 3 months (iSPN⁺mut, n = 5 and iSPN⁺wt, n = 5 biological replicas), genes were significantly upregulated (red arrow) (Gsto2, adj P = 4.2 × 10⁻⁷; Ggt7, adj P = 0.02) or downregulated (blue arrow) at 8 months, (iSPN⁺mut, n = 6 and iSPN⁺wt, n = 4 biological replicas), Gstm2 (adj P = 0.0007) and Ggt7 (adj P = 0.01). g, Representative western blot for 3 month striatal tissues lysate and quantification of GSTO2 protein levels expressed as fold change of control in a scatter plot (Trkb^Penk-WT, 1.0 ± 0.114; Trkb^Penk-KO, 2.698 ± 0.376, n = 4 of each genotype, all male mice, **P = 0.005). γ-Tubulin, loading control. Values are means; error bars, s.e.m. In a–d, n = 4–6 biological replicates per genotype or age; all male mice; P statistic from unpaired t-tests adjusting the P value with the false discovery rate method (two-stage step-up Benjamini, Krieger and Yekutieli). In g, P statistic from unpaired, two-tailed Student’s t-test.

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