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

Date Published: September 19, 2018

Publisher: Public Library of Science

Author(s): Li Zeng, Dapeng Zhang, Hayley S. McLoughlin, Annie J. Zalon, L. Aravind, Henry L. Paulson, Pedro Fernandez-Funez.


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.

Partial Text

Spinocerebellar ataxia type 3 (SCA3) is one of nine polyglutamine (polyQ) neurodegenerative diseases caused by an abnormally long polyQ tract in the disease protein, which in SCA3 is ATXN3 [1]. PolyQ diseases are age-related, progressive disorders that typically first manifest in midlife, leading to death 15–30 years later [2–5]. A common neuropathological hallmark in SCA3 and other polyglutamine diseases is the accumulation of ubiquitin-positive nuclear inclusions in neurons [6, 7]. Atxn3 null mice or C. elegans do not display obvious neurodegeneration, suggesting that a dominant gain-of-function, rather than a loss-of-function, mechanism principally drives SCA3 pathology, and that normal functions of ATXN3 are not essential [8, 9]. It remains possible, however, that polyQ expansion alters normal functional properties of the disease protein that contribute to the disease process. Many polyQ disease proteins participate in transcription [10], with disease-causing expansions disrupting normal transcriptional profiles in the nervous system. Here we sought to learn more about the potential normal role of ATXN3 in transcriptional regulation.

Here we have shown that loss of ATXN3 in MEFs results in widespread gene expression changes affecting many signal transduction pathways. We validated many of these transcriptional changes and defined a potential mechanism for differential expression of Efna3, a major component of the ephrin signaling pathway. Efna3 was the most elevated transcript in Atxn3-KO MEFs relative to wildtype controls and was also found to be elevated in Atxn3-KO mouse brainstem, a selectively vulnerable region in SCA3. Our results in MEFs further show that this marked Efna3 upregulation in the absence of ATXN3 correlates with enhanced acetylation of histone H3 and H4. Additional evidence supports the view that at least two histone acetylation regulators, HDAC3 and NCoR, are responsible for modulating the acetylation state of these histones in the presence of ATXN3. Together, our findings suggest that ATXN3 normally functions to regulate histone acetylation through histone deacetylases, including HDAC3 and NCoR, and thereby regulate the transcription of a large set of genes. The results warrant further assessment of the role that loss of ATXN3 transcriptional regulation may play in SCA3 disease pathogenesis.




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