Cerebellar RNA-Seq from ATXN1 Transgenic Mice Reveals SCA1 Disease Progression and Protection Pathways

SCA1, a fatal neurodegenerative disorder, is caused by a CAG expansion encoding a polyglutamine stretch in the protein ATXN1. We used RNA-seq to profile cerebellar RNA expression in ATXN1 mice, including lines with ataxia and progressive pathology and lines having ataxia in absence of Purkinje cell progressive pathology. Weighted Gene Coexpression Network Analysis of the cerebellar RNA-seq data revealed two gene networks that significantly correlated with disease, the Magenta (342 genes) and Light Yellow (35 genes) Modules. Features of the Magenta and Light Yellow Modules indicate they reflect distinctive pathways. The Magenta Module provides a description of suppressed transcriptional programs reflecting disease progression in Purkinje cells, while the Lt Yellow Module reflects other transcriptional programs activated in response to disease in Purkinje cells as well as other cerebellar cell types. We also found that up-regulation of cholecystokinin (Cck) blocked progression of Purkinje cell pathology and that loss of Cck function in mice lacking progressive disease enabled Purkinje cell pathology to progress to cell death. Overall design: Cerebellar mRNA expression profiles from ATXN1[82Q], ATXN1[30Q], and ATXN1[30Q]-D776 transgenic mice and wild type/FVB mice at 5 weeks, 12 weeks and 28 weeks of age ---------------------------- cuffnorm_ATXN1.82Q_ATXN1.30Q.D776_WTFVB_genes.fpkm_tracking.txt: CuffNorm normalized values for all samples (snoRNAs and miRNAs removed) cuffdiff_week5_ATXN1.82Q_ATXN1.30Q.D776_WTFVB_gene_exp.diff.txt: Cuffdiff comparison between samples at week 5; pairwise comparisons between ATXN1[82Q], ATXN1[30Q]D776 and FVB cuffdiff_week12_ATXN1.82Q_ATXN1.30Q.D776_WTFVB_gene_exp.diff.txt: Cuffdiff comparison between samples at week 12; pairwise comparisons between ATXN1[82Q], ATXN1[30Q]D776 and FVB cuffdiff_week28_ATXN1.82Q_ATXN1.30Q.D776_WTFVB_gene_exp.diff.txt: Cuffdiff comparison between samples at week 28; pairwise comparisons between ATXN1[82Q], ATXN1[30Q]D776 and FVB cuffdiff_week5_vs_week12_vs_week28_ATXN1.82Q_gene_exp.diff.txt: Cuffdiff comparison between ATXN1[82Q] at week 5, week 12 and week 28 cuffdiff_week5_vs_week12_vs_week28_ATXN1.30Q.D776_gene_exp.diff.txt: Cuffdiff comparison between ATXN1[30Q]D776 at week 5, week 12 and week 28 cuffdiff_week5_vs_week12_vs_week28_FVB_gene_exp.diff.txt: Cuffdiff comparison between wt/FVB at week 5, week 12 and week 28

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Ingram M, Wozniak EAL, Duvick L, Yang R, Bergmann P, Carson R, O'Callaghan B, Zoghbi HY, Henzler C, Orr HT