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.