Huntingtin protein is mutated in Huntington disease(1). We previously reported that wild-type but not mutant huntingtin stimulates transcription of the gene encoding brain-derived neurotrophic factor (BDNF; ref. 2). Here we show that the neuron restrictive silencer element (NRSE) is the target of wildtype huntingtin activity on BDNF promoter II. Wild-type huntingtin inhibits the silencing activity of NRSE, increasing transcription of BDNF. We show that this effect occurs through cytoplasmic sequestering of repressor element-1 transcription factor/neuron restrictive silencer factor (REST/NRSF), the transcription factor that binds to NRSE3,4. In contrast, aberrant accumulation of REST/NRSF in the nucleus is present in Huntington disease. We show that wild-type huntingtin coimmunoprecipitates with REST/NRSF and that less immunoprecipitated material is found in brain tissue with Huntington disease. We also report that wild-type huntingtin acts as a positive transcriptional regulator for other NRSE-containing genes involved in the maintenance of the neuronal phenotype(5). Consistently, loss of expression of NRSE-controlled neuronal genes is shown in cells, mice and human brain with Huntington disease. We conclude that wild-type huntingtin acts in the cytoplasm of neurons to regulate the availability of REST/NRSF to its nuclear NRSE-binding site and that this control is lost in the pathology of Huntington disease. These data identify a new mechanism by which mutation of huntingtin causes loss of transcription of neuronal genes.
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|Titolo:||Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes.|
|Autori:||Zuccato, C; Tartari, M; Crotti, A; Goffredo, D; Valenza, M; Conti, Luciano; Cataudella, T; Leavitt, Br; Hayden, Mr; Timmusk, T; Rigamonti, D; Cattaneo, E.|
|Titolo del periodico:||NATURE GENETICS|
|Anno di pubblicazione:||2003|
|Numero e parte del fascicolo:||1|
|Codice identificativo Scopus:||2-s2.0-0041353535|
|Codice identificativo Pubmed:||12881722|
|Codice identificativo ISI:||WOS:000185018500014|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/ng1219|
|Appare nelle tipologie:||03.1 Articolo su rivista (Journal article)|