English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disorder caused by a polyglutamine-encoding CAG repeat expansion in the  ATXN3  gene which encodes the deubiquitinating enzyme, ATXN3. Several mechanisms have been proposed to explain the pathogenic role of mutant, polyQ-expanded ATXN3 in SCA3 including disease protein aggregation, impairment of ubiquitin-proteasomal degradation and transcriptional dysregulation. A better understanding of the normal functions of this protein may shed light on SCA3 disease pathogenesis. To assess the potential normal role of ATXN3 in regulating gene expression, we compared transcriptional profiles in WT versus  Atxn3  null mouse embryonic fibroblasts. Differentially expressed genes in the absence of ATXN3 contribute to multiple signal transduction pathways, suggesting a status switch of signaling pathways including depressed Wnt and BMP4 pathways and elevated growth factor pathways such as Prolactin, TGF-β, and Ephrin pathways. The Eph receptor A3 ( Efna3 ), a receptor protein-tyrosine kinase in the Ephrin pathway that is highly expressed in the nervous system, was the most differentially upregulated gene in  Atxn3  null MEFs. This increased expression of  Efna3  was recapitulated in  Atxn3  knockout mouse brainstem, a selectively vulnerable brain region in SCA3. Overexpression of normal or expanded ATXN3 was sufficient to repress  Efna3  expression, supporting a role for ATXN3 in regulating Ephrin signaling. We further show that, in the absence of ATXN3,  Efna3  upregulation is associated with hyperacetylation of histones H3 and H4 at the  Efna3  promoter, which in turn is induced by decreased levels of HDAC3 and NCoR in ATXN3 null cells. Together, these results reveal a normal role for ATXN3 in transcriptional regulation of multiple signaling pathways of potential relevance to disease processes in SCA3.

Loss of the Spinocerebellar Ataxia type 3 disease protein ATXN3 alters transcription of multiple signal transduction pathways