Sp1 is up-regulated in cellular and transgenic models of Huntington disease, and its reduction is neuroprotective.
Interactions between mutant huntingtin (Htt) and a variety of transcription factors including specificity proteins (Sp) have been suggested as a central mechanism in Huntington disease (HD). However, the transcriptional activity induced by Htt in neurons that triggers neuronal death has yet to be fully elucidated. In the current study, we characterized the relationship of Sp1 to Htt protein aggregation and neuronal cell death. We found increased levels of Sp1 in neuronal-like PC12 cells expressing mutant Htt, primary striatal neurons, and brain tissue of HD transgenic mice. Sp1 levels were also elevated when 3-nitropropionate (3-NP) was used to induce cell death in PC12 cells. To assess the effects of knocking down Sp1 in HD pathology, we used Sp1 siRNA, a heterozygous Sp1 knock-out mouse, and mithramycin A, a DNA-intercalating agent that inhibits Sp1 function. The three approaches consistently yielded reduced levels of Sp1 which ameliorated toxicity caused by either mutant Htt or 3-NP. In addition, when HD mice were crossed with Sp1 heterozygous knock-out mice, the resulting offspring did not experience the loss of dopamine D2 receptor mRNA characteristic of HD mice, and survived longer than their HD counterparts. Our data suggest that enhancement of transcription factor Sp1 contributes to the pathology of HD and demonstrates that its suppression is beneficial.
Qiu
Zhihua
Z
Massachusetts General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA.
Norflus
Fran
F
Singh
Bhupinder
B
Swindell
Mary K
MK
Buzescu
Rodica
R
Bejarano
Michelle
M
Chopra
Raman
R
Zucker
Birgit
B
Benn
Caroline L
CL
DiRocco
Derek P
DP
Cha
Jang-Ho J
JH
Ferrante
Robert J
RJ
Hersch
Steven M
SM
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D016329:Sp1 Transcription Factor / Q000096:biosynthesis* / Q000502:physiology*; D015854:Up-Regulation
D018696:Neuroprotective Agents; D016329:Sp1 Transcription Factor