Effects of local reduction of endogenous α-synuclein using antisense oligonucleotides on the fibril-induced propagation of pathology through the neural network in wild-type mice.

IF 6.2 2区 医学 Q1 NEUROSCIENCES
Tatsuhiko Sano, Tetsuya Nagata, Satoe Ebihara, Kie Yoshida-Tanaka, Ayako Nakamura, Asuka Sasaki, Aki Shimozawa, Hideki Mochizuki, Toshiki Uchihara, Masato Hasegawa, Takanori Yokota
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引用次数: 0

Abstract

In Parkinson's disease and other synucleinopathies, fibrillar forms of α-synuclein (aSyn) are hypothesized to structurally convert and pathologize endogenous aSyn, which then propagates through the neural connections, forming Lewy pathologies and ultimately causing neurodegeneration. Inoculation of mouse-derived aSyn preformed fibrils (PFFs) into the unilateral striatum of wild-type mice causes widespread aSyn pathologies in the brain through the neural network. Here, we used the local injection of antisense oligonucleotides (ASOs) against Snca mRNA to confine the area of endogenous aSyn protein reduction and not to affect the PFFs properties in this model. We then varied the timing and location of ASOs injection to examine their impact on the initiation and propagation of aSyn pathologies in the whole brain and the therapeutic effect using abnormally-phosphorylated aSyn (pSyn) as an indicator. By injecting ASOs before or 0-14 days after the PFFs were inoculated into the same site in the left striatum, the reduction in endogenous aSyn in the striatum leads to the prevention and inhibition of the regional spread of pSyn pathologies to the whole brain including the contralateral right hemisphere. ASO post-injection inhibited extension from neuritic pathologies to somatic ones. Moreover, injection of ASOs into the right striatum prevented the remote regional spread of pSyn pathologies from the left striatum where PFFs were inoculated and no ASO treatment was conducted. This indicated that the reduction in endogenous aSyn protein levels at the propagation destination site can attenuate pSyn pathologies, even if those at the propagation initiation site are not inhibited, which is consistent with the original concept of prion-like propagation that endogenous aSyn is indispensable for this regional spread. Our results demonstrate the importance of recruiting endogenous aSyn in this neural network propagation model and indicate a possible potential for ASO treatment in synucleinopathies.

使用反义寡核苷酸局部减少内源性α-突触核蛋白对野生型小鼠神经网络中纤维诱导的病理学传播的影响
在帕金森病和其他突触核蛋白病中,α-突触核蛋白(aSyn)的纤维形式被假定为结构转换和病理化的内源性 aSyn,然后通过神经连接传播,形成路易病变并最终导致神经退行性变。在野生型小鼠的单侧纹状体中接种小鼠衍生的 aSyn 预成纤维(PFFs)会导致大脑神经网络中广泛的 aSyn 病变。在这里,我们利用局部注射针对 Snca mRNA 的反义寡核苷酸(ASO)来限制内源性 aSyn 蛋白减少的区域,而不影响该模型中 PFFs 的特性。然后,我们改变了注射 ASOs 的时间和位置,以异常磷酸化的 aSyn(pSyn)为指标,研究它们对全脑 aSyn 病变的启动和传播的影响以及治疗效果。通过在左侧纹状体同一部位接种 PFFs 之前或之后 0-14 天注射 ASO,减少纹状体中的内源性 aSyn,从而防止和抑制 pSyn 病变向包括对侧右半球在内的整个大脑的区域性扩散。ASO 注射后可抑制神经病变向躯体病变的扩展。此外,向右侧纹状体注射 ASO 还能阻止 pSyn 病变从接种了 PFF 但未进行 ASO 处理的左侧纹状体向远处区域扩散。这表明,即使不抑制传播起始点的内源性 aSyn 蛋白水平,也能降低传播目的地的内源性 aSyn 蛋白水平,这与朊病毒样传播的原始概念一致,即内源性 aSyn 对于这种区域性传播是不可或缺的。我们的研究结果证明了在这种神经网络传播模型中招募内源性 aSyn 的重要性,并指出了 ASO 治疗突触核蛋白病的可能潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
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