Background In Huntington's disease (HD), mutant huntingtin (mHtt) disrupts the normal transcriptional programme of disease neurons by altering the function of several gene expression regulators such as Sp1. The Neuron Restrictive Silencer Factor (NRSF), a key regulator of neuronal differentiation, is also aberrantly activated in HD by a mechanism that remains unclear.

Aim We studied the mechanism underlying NRSF activation in HD mouse and cellular models.

Results We show that the level of NRSF mRNA is increased in HD mouse and in neuroblastoma/glioma NG108 cells differentiated into neurons and expressing a toxic mHtt fragment. We further provide evidence that Sp1 and Sp3 bind NRSF promoter and interplay to finely regulate NRSF transcription. In undifferentiated NG108 cells, Sp1 and Sp3 have an antagonistic effect, Sp1 being an activator and Sp3 a repressor. On neuronal differentiation, the amount and ratio of Sp1/Sp3 proteins decline, correlating with reduced expression of NRSF, and the transcriptional role of Sp3 shifts towards a faint activator. Importantly, in NG108 neuronal cells expressing mHtt, specific knockdown of Sp1 abolishes the NRSF upregulation.

Conclusions Thus our data provide new molecular information to the transcriptional regulation of NRSF during neuronal differentiation and indicate that mHtt triggers an unexpected pathogenic cascade involving activation of Sp1, which in turn upregulates NRSF to repress neuronal genes.