CREB is a key regulator of striatal vulnerability in chemical and genetic models of Huntington's disease.
Evidence of dysregulation of the CREB/CRE transcriptional pathway in animal models of Huntington's disease (HD) suggests that strategies designed to augment CRE-mediated transcription may be of therapeutic value. Here, we investigated the consequences of CREB activation and repression in chemical and transgenic mouse models of HD. In the 3-nitropropionic acid (3-NP) model, CREB phospho-activation in the striatum was potently repressed within the neurotoxic "core" region prior to cell death. Conversely, marked expression of phospho-CREB, as well the CREB-regulated cytoprotective gene Bcl-2, was detected in the "penumbral" region. To examine potential contributory roles for the CREB/CRE transcriptional pathway in striatal degeneration, we used both CREB loss- (A-CREB) and gain- (VP16-CREB) of-function transgenic mouse strains. 3-NP-induced striatal lesion size and motor dysfunction were significantly increased in A-CREB mice compared to controls. Conversely, striatal damage and motor deficits were diminished in VP16-CREB mice. Furthermore, transgenic A-CREB significantly accelerated motor impairment in the YAC128 mouse model of HD. Together, these results indicate that CREB functionality is lost during the early stages of striatal cell stress and that the repression of CREB-mediated transcription contributes to the pathogenic process.
Choi
Yun-Sik
YS
Department of Neuroscience, Ohio State University, Columbus, OH 43210, USA.
Lee
Boyoung
B
Cho
Hee-Yeon
HY
Reyes
Iza B
IB
Pu
Xin-An
XA
Saido
Takaomi C
TC
Hoyt
Kari R
KR
Obrietan
Karl
K
D000818:Animals; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000502:physiology*; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009574:Nitro Compounds / Q000633:toxicity; D011422:Propionates / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D009574:Nitro Compounds; D011422:Propionates; C015392:3-nitropropionic acid