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Twist1 Plays an Anti-apoptotic Role in Mutant Huntingtin Expression Striatal Progenitor Cells.

出版日期:2020-01-07

Mol Neurobiol. 2019 Dec 7. doi: 10.1007/s12035-019-01836-x. [Epub ahead of print]

https://dx.doi.org/10.1007/s12035-019-01836-x

The Twist basic helix-loop-helix transcription factor 1 (Twist1) has been implicated in embryogenesis and carcinogenesis, due to its effects on cell proliferation and anti-apoptosis signaling. Interestingly, a connection between Twist1 and neurotoxicity was recently made in mutant huntingtin (mHtt)-expressing primary cortical neurons; however, the role of Twist1 in Huntington’s disease (HD)-affected striatal neurons remains undescribed. In this study, we evaluated the expression and function of Twist1 in the R6/2 HD mouse model, which expresses the polyQ-expanded N-terminal portion of human HTT protein, and a pair of striatal progenitor cell lines (STHdhQ109 and STHdhQ7), which express polyQ-expanded or non-expanded full-length mouse Htt. We further probed upstream signaling events and Twist1 anti-apoptotic function in the striatal progenitor cell lines. Twist1 was increased in mHtt-expressing striatal progenitor cells (STHdhQ109) and was correlated with disease progression in striatum and cortex brain regions of R6/2 mice. In the cell model, downregulation of Twist1 induced death of STHdhQ109 cells but had no effect on wild-type striatal progenitor cells (STHdhQ7). Twist1 knockdown stimulated caspase-3 activation and apoptosis. Furthermore, we found that signal transducer and activator of transcription 3 (STAT3) were increased in HD striatal progenitor cells and acted as an upstream regulator of Twist1. As such, inhibition of STAT3 induced apoptosis in HD striatal progenitor cells. Our results suggest that mHtt upregulates STAT3 to induce Twist1 expression. Upregulated Twist1 inhibits apoptosis, which may protect striatal cells from death during disease progression. Thus, we propose that Twist1 might play a protective role against striatal degeneration in HD.
 


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115台北市南港區研究院路二段128號
Tel: 02-27899515
Fax: 02-27858059
icob@gate.sinica.edu.tw
Copyright © ICOB 2013. All rights reserved. 最佳瀏覽網頁方式請用最新版IE11或其他瀏覽器 /瀏覽人數:1544359--
 瀏覽人數:1544359