eprintid: 10044709 rev_number: 18 eprint_status: archive userid: 608 dir: disk0/10/04/47/09 datestamp: 2018-03-06 14:06:53 lastmod: 2020-02-12 14:03:05 status_changed: 2018-03-06 14:06:53 type: article metadata_visibility: show creators_name: Pflieger, LT creators_name: Dansithong, W creators_name: Paul, S creators_name: Scoles, DR creators_name: Figueroa, KP creators_name: Meera, P creators_name: Otis, TS creators_name: Facelli, JC creators_name: Pulst, SM title: Gene co-expression network analysis for identifying modules and functionally enriched pathways in SCA2 ispublished: pub divisions: UCL divisions: A01 divisions: B02 divisions: C08 divisions: D75 note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. abstract: Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the ATXN2 gene. The repeat resides in an encoded region of the gene resulting in polyglutamine (polyQ) expansion which has been assumed to result in gain of function, predominantly, for the ATXN2 protein. We evaluated temporal cerebellar expression profiles by RNA sequencing of ATXN2Q127 mice versus wild-type (WT) littermates. ATXN2Q127 mice are characterized by a progressive motor phenotype onset, and have progressive cerebellar molecular and neurophysiological (Purkinje cell firing frequency) phenotypes. Our analysis revealed previously uncharacterized early and progressive abnormal patterning of cerebellar gene expression. Weighted Gene Coexpression Network Analysis revealed four gene modules that were significantly correlated with disease status, composed primarily of genes associated with GTPase signaling, calcium signaling and cell death. Of these genes, few overlapped with differentially expressed cerebellar genes that we identified in Atxn2−/− knockout mice versus WT littermates, suggesting that loss-of-function is not a significant component of disease pathology. We conclude that SCA2 is a disease characterized by gain of function for ATXN2. date: 2017-08-15 date_type: published official_url: http://dx.doi.org/10.1093/hmg/ddx191 oa_status: green full_text_type: other language: eng primo: open primo_central: open_green article_type_text: Article verified: verified_manual elements_id: 1505649 doi: 10.1093/hmg/ddx191 lyricists_name: Otis, Thomas lyricists_id: TOTIS27 actors_name: Otis, Thomas actors_id: TOTIS27 actors_role: owner full_text_status: public publication: Human Molecular Genetics volume: 26 number: 16 pagerange: 3069-3080 issn: 1460-2083 citation: Pflieger, LT; Dansithong, W; Paul, S; Scoles, DR; Figueroa, KP; Meera, P; Otis, TS; ... Pulst, SM; + view all <#> Pflieger, LT; Dansithong, W; Paul, S; Scoles, DR; Figueroa, KP; Meera, P; Otis, TS; Facelli, JC; Pulst, SM; - view fewer <#> (2017) Gene co-expression network analysis for identifying modules and functionally enriched pathways in SCA2. Human Molecular Genetics , 26 (16) pp. 3069-3080. 10.1093/hmg/ddx191 <https://doi.org/10.1093/hmg%2Fddx191>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10044709/1/Pflieger%20transcriptome%20ms%202017.pdf