Effects of Alpha-Synuclein Targeted Antisense Oligonucleotides on Lewy Body-Like Pathology and Behavioral Disturbances Induced by Injections of Pre-Formed Fibrils in the Mouse Motor Cortex.
Effects of Alpha-Synuclein Targeted Antisense Oligonucleotides on Lewy Body-Like Pathology and Behavioral Disturbances Induced by Injections of Pre-Formed Fibrils in the Mouse Motor Cortex.
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DOI：
10.3233/jpd-212566
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Unni VK
中科院分区：
文献类型：
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作者：
Boutros SW;Raber J;Unni VK
α-突触核蛋白（αsyn）表征称为突触核蛋白病的神经退行性疾病。磷酸化形式（psyn）是被称为路易体（LB）的蛋白质聚集体的主要成分，路易体是帕金森病（PD）等疾病的标志。突触核蛋白病可能以朊病毒样的方式传播，导致症状随着时间的推移逐渐出现。αsyn预形成的纤维（PFF）在野生型（WT）小鼠中诱导LB样病理学，但关于其进行性扩散及其对行为表现的相关影响仍存在问题。描述WT小鼠双侧运动皮质PFF注射后诱导的LB样病理的行为、认知和病理长期效应，并评估小鼠αsyn-targeted反义寡核苷酸（ASO）改善这些效应的能力。我们使用PFF在雄性WT小鼠的运动皮质和连接脑区域中诱导LB样病理学。PFF注射（mpi）后三个月，我们评估了行为和认知表现。然后，我们通过心室递送靶向阿索，并在5周后评估行为和认知表现，随后进行病理分析。在3和6 mpi时，注射PFF的小鼠表现出轻度的、进行性的行为缺陷。阿索降低了总αsyn和psyn蛋白水平以及LB样病理学，但也与一些不涉及αsyn降低的有害脱靶效应相关，如体重下降和运动功能障碍。这些结果增加了对PFF模型进行性的理解，并支持ASO的治疗潜力，尽管需要更多研究ASO介导的αsyn减少对脑功能的影响。
Alpha-synuclein (αsyn) characterizes neurodegenerative diseases known as synucleinopathies. The phosphorylated form (psyn) is the primary component of protein aggregates known as Lewy bodies (LBs), which are the hallmark of diseases such as Parkinson’s disease (PD). Synucleinopathies might spread in a prion-like fashion, leading to a progressive emergence of symptoms over time. αsyn pre-formed fibrils (PFFs) induce LB-like pathology in wild-type (WT) mice, but questions remain about their progressive spread and their associated effects on behavioral performance. To characterize the behavioral, cognitive, and pathological long-term effects of LB-like pathology induced after bilateral motor cortex PFF injection in WT mice and to assess the ability of mouse αsyn-targeted antisense oligonucleotides (ASOs) to ameliorate those effects. We induced LB-like pathology in the motor cortex and connected brain regions of male WT mice using PFFs. Three months post-PFF injection (mpi), we assessed behavioral and cognitive performance. We then delivered a targeted ASO via the ventricle and assessed behavioral and cognitive performance 5 weeks later, followed by pathological analysis. At 3 and 6 mpi, PFF-injected mice showed mild, progressive behavioral deficits. The ASO reduced total αsyn and psyn protein levels, and LB-like pathology, but was also associated with some deleterious off-target effects not involving lowering of αsyn, such as a decline in body weight and impairments in motor function. These results increase understanding of the progressive nature of the PFF model and support the therapeutic potential of ASOs, though more investigation into effects of ASO-mediated reduction in αsyn on brain function is needed.