Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease
Anthone W. Dunah,1
Hyunkyung Jeong,1
April Griffin,1
Yong-Man Kim,2
David G. Standaert,1
Steven M. Hersch,1
M. Maral Mouradian,2
Anne B. Young,1
Naoko Tanese,3
Dimitri Krainc1*
Huntington's disease (HD) is an inherited
neurodegenerative disease caused by expansion of a polyglutamine tract
in the huntingtin protein. Transcriptional dysregulation has been
implicated in HD pathogenesis. Here, we report that huntingtin
interacts with the transcriptional activator Sp1 and coactivator
TAFII130. Coexpression of Sp1 and TAFII130 in cultured striatal cells
from wild-type and HD transgenic mice reverses the transcriptional
inhibition of the dopamine D2 receptor gene caused by mutant
huntingtin, as well as protects neurons from huntingtin-induced
cellular toxicity. Furthermore, soluble mutant huntingtin inhibits Sp1
binding to DNA in postmortem brain tissues of both presymptomatic and
affected HD patients. Understanding these early molecular events in HD may provide an opportunity to interfere with the effects of mutant huntingtin before the development of disease symptoms.
1 Department of Neurology, Massachusetts
General Hospital, Harvard Medical School, Center for Aging, Genetics
and Neurodegeneration, Charlestown, MA 02129, USA.
2 Genetic Pharmacology Unit, Experimental
Therapeutics Branch, National Institute of Neurological Disorders and
Stroke, National Institutes of Health, 10 Center Drive, MSC 1406, Bethesda, MD 20892-1406, USA.
3 Department of
Microbiology/MSB258, New York University School of Medicine, 550 First
Avenue, New York, NY 10016, USA.
*
To whom correspondence should be addressed. E-mail:
krainc{at}helix.mgh.harvard.edu
