Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice.
Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice.
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DOI：
10.1002/mds.25978
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发表时间：
2014-10
影响因子：
8.6
通讯作者：
Alvarez-Erviti, Lydia
中科院分区：
文献类型：
--
作者：
Cooper, J. Mark;Wiklander, P. B. Oscar;Nordin, Joel Z.;Al-Shawi, Raya;Wood, Matthew J.;Vithlani, Mansi;Schapira, Anthony H. V.;Simons, J. Paul;El-Andaloussi, Samir;Alvarez-Erviti, Lydia
α-突触核蛋白（α-Syn）聚集体是路易体的主要成分，路易体是帕金森病（PD）的特征性病理特征。α-Syn聚集可以在神经元之间传播的证据表明，这种机制是PD病理逐步进展的原因。预测降低α-Syn表达可减弱该过程，因此是延迟或停止PD进展的有吸引力的方法。我们已经使用α-Syn小干扰RNA（siRNA）来降低小鼠脑中总的和聚集的α-Syn水平。为了实现siRNA向脑的广泛递送，我们外周注射了表达负载有siRNA的Ravies病毒糖蛋白的修饰的外泌体。在注射后3或7天分析正常小鼠。为了评估这种方法是否可以减少α-Syn聚集体，我们使用表达人磷酸化模拟物S129 D α-Syn的转基因小鼠重复了该治疗，该小鼠表现出聚集。在正常小鼠中，我们检测到在用加载有针对α-Syn的siRNA的RVG-外泌体处理后3天和7天，整个大脑中的α-Syn信使RNA（mRNA）和蛋白质水平显著降低。在S129 D α-Syn转基因小鼠中，我们发现注射后7天整个脑中的α-Syn mRNA和蛋白水平降低。这导致神经元内蛋白质聚集体显着减少，包括黑质的多巴胺能神经元。这项研究强调了RVG-外泌体递送siRNA延迟和逆转脑α-Syn病理状况的治疗潜力。© 2014作者。出版社：Wiley Periodicals，Inc.国际帕金森和运动障碍协会（International Parkinson and Movement Disorder Society）
Alpha-synuclein (α-Syn) aggregates are the main component of Lewy bodies, which are the characteristic pathological feature in Parkinson's disease (PD) brain. Evidence that α-Syn aggregation can be propagated between neurones has led to the suggestion that this mechanism is responsible for the stepwise progression of PD pathology. Decreasing α-Syn expression is predicted to attenuate this process and is thus an attractive approach to delay or halt PD progression. We have used α-Syn small interfering RNA (siRNA) to reduce total and aggregated α-Syn levels in mouse brains. To achieve widespread delivery of siRNAs to the brain we have peripherally injected modified exosomes expressing Ravies virus glycoprotein loaded with siRNA. Normal mice were analyzed 3 or 7 days after injection. To evaluate whether this approach can decrease α-Syn aggregates, we repeated the treatment using transgenic mice expressing the human phosphorylation-mimic S129D α-Syn, which exhibits aggregation. In normal mice we detected significantly reduced α-Syn messenger RNA (mRNA) and protein levels throughout the brain 3 and 7 days after treatment with RVG-exosomes loaded with siRNA to α-Syn. In S129D α-Syn transgenic mice we found a decreased α-Syn mRNA and protein levels throughout the brain 7 days after injection. This resulted in significant reductions in intraneuronal protein aggregates, including in dopaminergic neurones of the substantia nigra. This study highlights the therapeutic potential of RVG-exosome delivery of siRNA to delay and reverse brain α-Syn pathological conditions. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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影响因子：
46.9
作者：
Alvarez-Erviti, Lydia;Seow, Yiqi;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.
影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
影响因子：
56.9
作者：
Singleton, AB;Farrer, M;Gwinn-Hardy, K
通讯作者：
Gwinn-Hardy, K
影响因子：
6.1
作者：
Febbraro, Fabia;Sahin, Gurdal;Romero-Ramos, Marina
通讯作者：
Romero-Ramos, Marina
影响因子：
15.1
作者：
Lewis, Jada;Melrose, Heather;Bumcrot, David;Hope, Andrew;Zehr, Cynthia;Lincoln, Sarah;Braithwaite, Adam;He, Zhen;Ogholikhan, Sina;Hinkle, Kelly;Kent, Caroline;Toudjarska, Ivanka;Charisse, Klaus;Braich, Ravi;Pandey, Rajendra K.;Heckman, Michael;Maraganore, Demetrius M.;Crook, Julia;Farrer, Matthew J.
通讯作者：
Farrer, Matthew J.