It is well known that an expanded polyglutamine tract (polyQ) within the huntingtin (htt) protein is the root cause of Huntington's disease (HD), but just exactly how this polyQ expansion exerts its devastating effects on neurons remains something of a mystery. Hints from transgenic mice, which express mutant huntingtin and have altered levels of expression of many genes, suggest that the aberrant protein may sequester other proteins that are essential for transcription-though what these protein(s) are remains to be seen.

In yesterday's Sciencexpress Dimitri Krainc at Massachusetts General Hospital, and coworkers at the NIH in Bethesda, Maryland, and New York University School of Medicine, identify potential protein victims of mutant huntingtin. They found that polyQ htt compromises the interaction between the transcriptional activator Sp1 and the TATA-box binding protein factor TAFII130. The former is an activator of many genes, including the D2 dopamine receptor, the latter forms part of a large complex that is recruited to gene promoters and is essential for all transcription.

Krainc and colleagues showed that polyQ htt binds more tightly to Sp1 than does wild-type htt, and that this interaction can prevent Sp1 from finding, and binding, its targets. As a result, Sp1 binds poorly to TAFII130 and to its promoter sequences; as demonstrated by the failure of Sp1 to promote transcription of the D2 dopamine receptor in cultured cells expressing mutant huntingtin. This suppression could be relieved by overexpressing both Sp1 and TAFII130; overexpression also abolished huntingtin-induced cell toxicity and death.

The authors extended their observations to tissue from diseased human brains. Immunoprecipitates from post-mortem tissue showed that there was poorer interaction between Sp1 and TAFII130 than in normal brain tissue. Western blotting suggested that most of the Sp1 from normal tissue was sequestered in soluble form, rather than in the inclusion bodies that form in diseased neurons, suggesting that soluble huntingtin is the culprit in the sequestration of Sp1.

This data should allow researchers to focus on specific genes that may be important in the etiology of HD, namely those harboring the Sp1 sequence, with the hopes of revealing promising therapeutic targets.—Tom Fagan


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Primary Papers

  1. . Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science. 2002 Jun 21;296(5576):2238-43. PubMed.