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