SMAD transcription factors are altered in cell models of HD and regulate HTT expression

Kr Bowles,T Stone,P Holmans,Nd Allen,Sb Dunnett,L Jones

doi:10.1016/j.cellsig.2016.12.005

Kr Bowles, T Stone + Show 4 more

Open Access

https://doi.org/10.1016/j.cellsig.2016.12.005

Copy DOI

Journal: Cellular Signalling	Publication Date: Dec 14, 2016
Citations: 20	License type: cc-by

Affiliation: Cardiff University

Abstract

Transcriptional dysregulation is observable in multiple animal and cell models of Huntington's disease, as well as in human blood and post-mortem caudate. This contributes to HD pathogenesis, although the exact mechanism by which this occurs is unknown. We therefore utilised a dynamic model in order to determine the differential effect of growth factor stimulation on gene expression, to highlight potential alterations in kinase signalling pathways that may be in part responsible for the transcriptional dysregulation observed in HD, and which may reveal new therapeutic targets. We demonstrate that cells expressing mutant huntingtin have a dysregulated transcriptional response to epidermal growth factor stimulation, and identify the transforming growth factor-beta pathway as a novel signalling pathway of interest that may regulate the expression of the Huntingtin (HTT) gene itself. The dysregulation of HTT expression may contribute to the altered transcriptional phenotype observed in HD.

Highlights

Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG expansion within the first exon of the Huntingtin (HTT) gene, which gives rise to an expanded polyglutamine tract in the huntingtin (HTT) protein
By investigating differential gene expression between StHdhQ7/7 and StHdhQ111/111 cell lines using microarray analysis, we identified TGFβ signalling as a significantly altered signalling pathway, despite using epidermal growth factor (EGF) as a stimulus
This is not surprising, as substantial crosstalk between EGF and TGFβ pathways has previously been identified [18,19,20,21]; for example, while SMAD7 is an inhibitor of SMAD signalling by competitive interaction with the TGFβ type 1 receptor [22] and by interfering with

Summary

Introduction

Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG expansion within the first exon of the Huntingtin (HTT) gene, which gives rise to an expanded polyglutamine tract in the huntingtin (HTT) protein. HD is characterised by progressive motor abnormalities that manifest in the third to fourth decades of life, and is commonly associated with cognitive impairments and psychiatric disturbances [1]. Neuronal dysfunction has been found to occur prior to both striatal atrophy and overt motor symptom onset [2,3]. It is possible that cell death and degeneration in HD-affected neuronal cells follow an initial period of dysregulation of multiple cellular processes [4]. The regulation of kinase signalling is altered by, and in turn alters, gene expression: in HD aberrant regulation of multiple kinase signalling pathways has been shown [5]. The TGFβ pathway is a regulator of cell growth, proliferation and apoptosis, and is upstream of

Methods

Results

Conclusion