Transcriptional Activation of REST by Sp1 in Huntington's Disease Models

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

Toleration, neutrality and historical illiteracy

John Gray has acquired international prominence and notoriety for his trenchant and uncompromising critique of the liberal tradition. According to Gray, the pervasive value pluralism that characterizes the contemporary world has rendered liberalism, and in particular its theory of toleration, both historically redundant and theoretically obsolete as a means of ensuring peaceful coexistence between competing values and practices. Gray insists that his alternative political framework of modus vivendi is far more capable of achieving these outcomes. This paper challenges Gray’s account of the liberal tradition, and its theory of toleration, revealing the shortcomings of that account at a historical and philosophical level. It argues that liberalism emerged in a European context characterized by precisely the sort of pluralism that Gray associates with the contemporary world, and was specifically conceived to deal with it in a manner which is still relevant today. In this way, it is possible to rescue the liberal tradition from the theoretical obsolescence and historical redundancy to which Gray seeks to consign it