Increased expression of Bim contributes to the potentiation of serum deprivation-induced apoptotic cell death in Huntington's disease knock-in striatal cell line.
Given that mutant huntingtin may cause dysregulation of gene expression in striatal neurons leading to the neuronal death, we examined the expression level of Bcl-2 interacting mediator of cell death (Bim) in immortalized wild type STHdh(Q7) and knock-in mutant STHdh(Q111) striatal cell lines to understand the underlying mechanism by which mutant huntingtin causes selective death of striatal neurons. Mutant STHdh(Q111) exhibited significantly increased expression level of Bim compared to STHdh(Q7). Serum deprivation resulted in potentiated apoptotic death in STHdh(Q111) compared to STHdh(Q7). However, the expression level of Bim was not changed with serum deprivation in both cell lines. Activation of pro-survival pathway with IGF-1 significantly attenuated serum deprivation-induced neuronal death in both cell lines and attenuated mutant huntingtin-mediated potentiated apoptotic death in STHdh(Q111). The level of active Akt was significantly elevated in STHdh(Q111) compared to STHdh(Q7) resulting in the phosphorylation of a FKHRL1, a forkhead transcription factor regulating Bim expression in neuronal cells. These data suggest that the presence of mutant huntingtin causes transcriptional dysregulation favoring apoptosis and that Akt pro-survival pathway in STHdh(Q111) is not compromised due to the presence of mutant huntingtin. Therefore, activation of this pathway may contribute to the protection of striatal neurons in Huntington's disease.
Kong
Pil-Jae
PJ
Department of Pharmacology, College of Medicine, Kangwon National University, Chunchon, Korea.
Kil
Myung-Og
MO
Lee
Heejae
H
Kim
Sung-Soo
SS
Johnson
Gail V W
GV
Chun
Wanjoo
W
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D002460:Cell Line; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics*; D055879:Gene Knock-In Techniques; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt