Transcriptional Dysfunction in Huntington's Disease

Science's STKE  25 Jun 2002:
Vol. 2002, Issue 138, pp. TW226
DOI: 10.1126/stke.2002.138.TW226


The neurodegeneration characteristic of Huntington's disease (HD) is caused by mutations that induce expansion of a polyglutamine tract in the huntingtin protein. Mutant huntingtin is believed to interfere with transcription of genes that may be important for neuronal survival. Dunah et al. (see the Perspective by Frieman and Tjian) report that mutant huntingtin interferes with transcription mediated by the transcriptional activator Sp1 and its coactivator TAFII130. Coexpression of Sp1 and TAFII130 in cultured striatal cells from HD transgenic mice reversed the transcriptional block caused by mutant huntingtin. Soluble mutant huntingtin prevented binding of Sp1 to DNA in postmortem brain tissue from patients with presymptomatic and symptomatic HD, which suggests that transcriptional dysfunction caused by mutant huntingtin is an early event in HD pathogenesis.

A. W. Dunah, H. Jeong, A. Griffin, Y.-M. Kim, D. G. Standaert, S. M. Hersch, M. M. Mouradian, A. B. Young, N. Tanese, D. Krainc, Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science 296, 2238 (2002). [Full Text] [Abstract]

R. N. Freiman, R. Tjian, A glutamine-rich trail leads to transcription factors. Science 296, 2149-2150 (2002). [Full Text]