title: Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways.
abstract: SCA1, a fatal neurodegenerative disorder, is caused by a CAG expansion encoding a polyglutamine stretch in the protein ATXN1. We used RNA sequencing to profile cerebellar gene expression in Pcp2-ATXN1[82Q] mice with ataxia and progressive pathology and Pcp2-ATXN1[30Q]D776 animals having ataxia in absence of Purkinje cell progressive pathology. Weighted Gene Coexpression Network Analysis of the cerebellar expression data revealed two gene networks that significantly correlated with disease and have an expression profile correlating with disease progression in ATXN1[82Q] Purkinje cells. The Magenta Module provides a signature of suppressed transcriptional programs reflecting disease progression in Purkinje cells, while the Lt Yellow Module reflects transcriptional programs activated in response to disease in Purkinje cells as well as other cerebellar cell types. Furthermore, we found that upregulation of cholecystokinin (Cck) and subsequent interaction with the Cck1 receptor likely underlies the lack of progressive Purkinje cell pathology in Pcp2-ATXN1[30Q]D776 mice.
authors.affiliation: Institute for Translational Neuroscience, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455.|Department of Genetics, Cell Biology, and Development, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Melissa
authors.initials: M
authors.lastname: Ingram
authors.affiliation: Institute for Translational Neuroscience, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455.|Department of Neuroscience, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Emily A L
authors.initials: EAL
authors.lastname: Wozniak
authors.affiliation: Institute for Translational Neuroscience, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455.|Department of Laboratory Medicine and Pathology, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Lisa
authors.initials: L
authors.lastname: Duvick
authors.affiliation: RISS Bioinformatics, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Rendong
authors.initials: R
authors.lastname: Yang
authors.affiliation: Foresight Logic, Inc., Shoreview, MN 55126.
authors.forename: Paul
authors.initials: P
authors.lastname: Bergmann
authors.affiliation: Institute for Translational Neuroscience, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455.|Department of Laboratory Medicine and Pathology, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Robert
authors.initials: R
authors.lastname: Carson
authors.affiliation: Institute for Translational Neuroscience, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455.|Department of Laboratory Medicine and Pathology, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Brennon
authors.initials: B
authors.lastname: O'Callaghan
authors.affiliation: Departments of Molecular and Human Genetics, Pediatrics, and Howard Hughes Medical Institute, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Childrens Hospital, Houston, TX 77030.
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
authors.affiliation: RISS Bioinformatics, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Christine
authors.initials: C
authors.lastname: Henzler
authors.affiliation: Institute for Translational Neuroscience, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455.|Department of Laboratory Medicine and Pathology, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Harry T
authors.initials: HT
authors.lastname: Orr
mesh_terms: D000818:Animals; D000067696:Ataxin-1 / Q000235:genetics* / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology*; D019742:Chemokines, CC / Q000172:deficiency / Q000235:genetics; D002766:Cholecystokinin / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D053263:Gene Regulatory Networks; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism; D043887:Receptor, Cholecystokinin B / Q000172:deficiency / Q000235:genetics; D020754:Spinocerebellar Ataxias / Q000473:pathology*; D059467:Transcriptome / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D000067696:Ataxin-1; C000593750:Atxn1 protein, mouse; C511142:Ccl28 protein, mouse; D019742:Chemokines, CC; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; C104971:Pcp2 protein, mouse; D010455:Peptides; D043887:Receptor, Cholecystokinin B; C097188:polyglutamine; D002766:Cholecystokinin