Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways

Melissa Ingram, Emily A L Wozniak, Lisa Duvick, Rendong Yang, Paul Bergmann, Robert Carson, Brennon O'Callaghan, Huda Y. Zoghbi, Christine Henzler, Harry T. Orr

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1194-1207
Number of pages14
JournalNeuron
Volume89
Issue number6
DOIs
StatePublished - Mar 16 2016

Bibliographical note

Funding Information:
We thank Orion Rainwater for propagating and maintaining mouse colony and Dr. Jeehye Park and Ms. Antonia De Maio for their constructive comments. This study was supported by NIH/NINDS grants 2R37NS022920 and 2RO1NS045667 (H.T.O.) and 2R37NS027699 (H.Y.Z.).

Funding Information:
We thank Orion Rainwater for propagating and maintaining mouse colony and Dr. Jeehye Park and Ms. Antonia De Maio for their constructive comments. This study was supported by NIH/NINDS grants 2R37NS022920 and 2RO1NS045667 (H.T.O.) and 2R37NS027699 (H.Y.Z.).

Publisher Copyright:
© 2016 Elsevier Inc.

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