Protein transduction domain-mediated delivery of QBP1 suppresses polyglutamine-induced neurodegeneration in vivo
Protein transduction domain-mediated delivery of QBP1 suppresses polyglutamine-induced neurodegeneration in vivo
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DOI：
10.1038/sj.mt.6300045
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发表时间：
2007-02-01
影响因子：
12.4
通讯作者：
Toda, Tatsushi
中科院分区：
文献类型：
--
作者：
Popiel, H. Akiko;Nagai, Yoshitaka;Toda, Tatsushi
许多神经退行性疾病如阿尔茨海默病、帕金森病和多聚谷氨酰胺（polyQ）疾病具有共同的特征，包括错误折叠的蛋白质的异常聚集及其在脑中作为包涵体的沉积。polyQ疾病是由每种致病蛋白中polyQ延伸的异常扩张引起的，这触发这些蛋白质形成聚集体。我们以前表明，聚集体抑制肽polyQ结合肽1（QBP 1）的基因表达抑制polyQ诱导的果蝇神经变性。然而，为了建立使用QBP 1的分子疗法，QBP 1需要通过其施用递送到细胞中。在这项研究中，我们采用蛋白转导结构域（PTDs），使QBP 1的有效细胞内交付。我们在这里表明，与PTD的融合能够有效的细胞内输送QBP 1，PTD-QBP 1治疗抑制polyQ诱导的细胞毒性培养细胞。最重要的是，PTD-QBP 1的口服给药成功地抑制了polyQ疾病的果蝇模型中polyQ诱导的过早死亡以及polyQ包涵体形成，证明了其对polyQ诱导的体内神经变性的治疗效果。我们的研究表明，PTD介导的聚合物抑制肽的递送是一种有前途的治疗策略，用于具有错误折叠蛋白质异常聚集的神经退行性疾病。
Many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and the polyglutamine ( polyQ) diseases share common features including abnormal aggregation of misfolded proteins and their deposition as inclusion bodies in the brain. The polyQ diseases are caused by abnormal expansion of a polyQ stretch in each disease-causing protein, which triggers these proteins to form aggregates. We previously showed that genetic expression of the aggregate inhibitor peptide polyQ binding peptide 1 (QBP1) suppresses polyQ-induced neurodegeneration in Drosophila. However, to establish a molecular therapy using QBP1, QBP1 needs to be delivered into cells by its administration. In this study, we employed protein transduction domains (PTDs) to enable the efficient intracellular delivery of QBP1. We show here that fusion with a PTD enables the efficient intracellular delivery of QBP1, and that PTD-QBP1 treatment suppressed polyQ-induced cytotoxicity in cultured cells. Most importantly, oral administration of PTD-QBP1 successfully suppressed polyQ-induced premature death as well as polyQ inclusion body formation in a Drosophila model of the polyQ diseases, demonstrating its therapeutic effect against polyQ-induced neurodegeneration in vivo. Our study indicates that PTD-mediated delivery of aggregate inhibitor peptides is a promising therapeutic strategy for neurodegenerative diseases with abnormal aggregation of misfolded proteins.