RpA1 ameliorates symptoms of mutant Ataxin-1 knock-in mice and enhances DNA damage repair
RpA1 ameliorates symptoms of mutant Ataxin-1 knock-in mice and enhances DNA damage repair
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RpA1改善突变Ataxin-1敲入小鼠的症状并增强DNA损伤修复
DOI：
10.1093/hmg/ddw272
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发表时间：
2016
影响因子：
3.5
通讯作者：
H.
中科院分区：
文献类型：
--
作者：
Taniguchi;JB.;Kondo;K.;Fujita;K.;Chen;X.;Homma;H.;Sudo;T.;Mao;Y.;Watase;K.;Tanaka;T.;Tagawa;K.;Tamura;T.;Muramatsu;SI.;Okazawa;H.
DNA损伤和修复是许多神经退行性疾病的关键领域。在这项研究中，我们专注于RpA 1，polyQ疾病病理学中的候选关键分子，并测试了表达RpA 1的腺相关病毒（AAV）载体对突变型Ataxin-1敲入（Atxn 1-KI）小鼠的治疗效果。我们发现对运动功能、正常化DNA损伤标志物（γ H2 AX和53 BP 1）和改善浦肯野细胞形态的显著影响; AAV-RpA 1感染后持续50周的影响。此外，我们证实AAV-RpA 1间接恢复Atxn 1-KI小鼠浦肯野细胞的多种细胞功能，如RNA剪接、转录和细胞周期以及树突和树突棘的异常形态。这些结果提示RpA 1基因治疗SCA 1的可能性。
DNA damage and repair is a critical domain of many neurodegenerative diseases. In this study, we focused on RpA1, a candidate key molecule in polyQ disease pathologies, and tested the therapeutic effect of adeno-associated virus (AAV) vector expressing RpA1 on mutant Ataxin-1 knock-in (Atxn1-KI) mice. We found significant effects on motor functions, normalized DNA damage markers (γH2AX and 53BP1), and improved Purkinje cell morphology; effects that lasted for 50 weeks following AAV-RpA1 infection. In addition, we confirmed that AAV-RpA1 indirectly recovered multiple cellular functions such as RNA splicing, transcription and cell cycle as well as abnormal morphology of dendrite and dendritic spine of Purkinje cells in Atxn1-KI mice. All these results suggested a possibility of gene therapy with RpA1 for SCA1.