SINEUP Non-coding RNA Targeting GDNF Rescues Motor Deficits and Neurodegeneration in a Mouse Model of Parkinson's Disease
SINEUP Non-coding RNA Targeting GDNF Rescues Motor Deficits and Neurodegeneration in a Mouse Model of Parkinson's Disease
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DOI：
10.1016/j.ymthe.2019.08.005
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发表时间：
2020-02-05
影响因子：
12.4
通讯作者：
Gustincich, Stefano
中科院分区：
文献类型：
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作者：
Espinoza, Stefano;Scarpato, Margherita;Gustincich, Stefano
胶质细胞源性神经营养因子（GDNF）具有促进多巴胺（DA）神经元存活的作用。一些研究表明，增加GDNF水平可能有利于通过减少DA神经元的神经变性来治疗帕金森病（PD）。尽管大量的临床前研究显示GDNF在PD动物模型中的功效，但由于其不受控制的异位表达，其在人类中的应用仍然存在疗效差和副作用的问题。在这里，我们利用SINEUP，一类新的反义长非编码RNA，促进部分重叠的正义蛋白编码mRNA的翻译，而不影响其mRNA水平。通过合成靶向GDNF mRNA的SINEUP，我们能够将内源性GDNF蛋白水平提高约2倍。腺相关病毒（AAV）9介导的野生型（WT）小鼠纹状体中的递送导致内源性GDNF蛋白增加至少6个月，并增强DA系统的功能，同时显示无副作用。此外，SINEUP-GDNF能够改善PD神经化学小鼠模型中DA神经元的运动缺陷和神经变性。我们的数据表明，SINEUP-GDNF可以代表一种新的策略，以更生理的方式增加内源性GDNF蛋白水平，用于PD的治疗性治疗。
Glial cell-derived neurotrophic factor (GDNF) has a potent action in promoting the survival of dopamine (DA) neurons. Several studies indicate that increasing GDNF levels may be beneficial for the treatment of Parkinson's disease (PD) by reducing neurodegeneration of DA neurons. Despite a plethora of preclinical studies showing GDNF efficacy in PD animal models, its application in humans remains questionable for its poor efficacy and side effects due to its uncontrolled, ectopic expression. Here we took advantage of SINEUPs, a new class of antisense long non-coding RNA, that promote translation of partially overlapping sense protein-coding mRNAs with no effects on their mRNA levels. By synthesizing a SINEUP targeting Gdnf mRNA, we were able to increase endogenous GDNF protein levels by about 2-fold. Adeno-associated virus (AAV) 9-mediated delivery in the striatum of wild-type (WT) mice led to an increase of endogenous GDNF protein for at least 6 months and the potentiation of the DA system's functions while showing no side effects. Furthermore, SINEUP-GDNF was able to ameliorate motor deficits and neurodegeneration of DA neurons in a PD neurochemical mouse model. Our data indicate that SINEUP-GDNF could represent a new strategy to increase endogenous GDNF protein levels in a more physiological manner for therapeutic treatments of PD.