Abstract
In Huntington's disease (HD), mutant huntingtin (mHtt) disrupts the normal transcriptional program of disease neurons by altering the function of several gene expression regulators such as Sp1. REST (Repressor Element-1 Silencing Transcription Factor), a key regulator of neuronal differentiation, is also aberrantly activated in HD by a mechanism that remains unclear. Here, we show that the level of REST mRNA is increased in HD mice and in NG108 cells differentiated into neuronal-like cells and expressing a toxic mHtt fragment. Using luciferase reporter gene assay, we delimited the REST promoter regions essential for mHtt-mediated REST upregulation and found that they contain Sp factor binding sites. We provide evidence that Sp1 and Sp3 bind REST promoter and interplay to fine-tune REST transcription. In undifferentiated NG108 cells, Sp1 and Sp3 have antagonistic effect, Sp1 acting as an activator and Sp3 as a repressor. Upon neuronal differentiation, we show that the amount and ratio of Sp1/Sp3 proteins decline, as does REST expression, and that the transcriptional role of Sp3 shifts toward a weak activator. Therefore, our results provide new molecular information to the transcriptional regulation of REST during neuronal differentiation. Importantly, specific knockdown of Sp1 abolishes REST upregulation in NG108 neuronal-like cells expressing mHtt. Our data together with earlier reports suggest that mHtt triggers a pathogenic cascade involving Sp1 activation, which leads to REST upregulation and repression of neuronal genes.
Highlights
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by involuntary movements, psychiatric disturbances and cognitive decline
We found that REST mRNA was significantly increased in the striatum of 12-week old R6/2 mouse model of HD compared to wild-type mice (Fig. 1A)
Using cellular and mouse models of HD, we show that REST mRNA is significantly increased in neurons expressing mutant Htt (mHtt) fragments
Summary
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by involuntary movements, psychiatric disturbances and cognitive decline. HD belongs to a group of 10 inherited neurodegenerative disorders, including 7 dominant spinocerebellar ataxias (SCAs), that are caused by polyQ expansion in specific disease proteins [2]. Expression profiling studies of HD mouse brains showed that hundreds of genes were deregulated, including a conspicuous decreased expression of neuronal specific genes in the striatum [9,10,11,12]. In a SCA1 mouse model, specific genes involved in glutamate signaling functions were deregulated in Purkinje cells, one major target of the disease [14]. In a mouse model recapitulating the retinal degeneration affecting SCA7 patients, the retinopathy correlated with a global repression of genes involved in photoreceptor function and morphogenesis, suggesting an alteration of the neuronal differentiation program [15,16]
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