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(LBs)的蛋白质聚集体的主要成分,这是帕金森病(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,随着时间的推移导致症状逐渐出现。αsyn预形成原纤维(PFFs)在野生型(WT)小鼠中诱导LB样病理,但是关于它们的逐渐传播及其对行为表现的相关影响的问题仍然存在。
为了表征行为,认知,和WT小鼠双侧运动皮质PFF注射后诱导的LB样病理的病理长期作用,并评估小鼠αsyn靶向反义寡核苷酸(ASO)改善这些作用的能力。
我们使用PFF在雄性WT小鼠的运动皮质和连接的脑区域中诱导了LB样病理。PFF注射后三个月(mpi),我们评估了行为和认知表现。然后,我们通过心室进行靶向ASO,并在5周后评估行为和认知表现,然后进行病理分析。
在3和6mpi时,注射PFF的小鼠表现出温和,渐进的行为缺陷。ASO降低了总αsyn和psyn蛋白水平,和LB样病理,但也与一些不涉及降低αsyn的有害脱靶效应有关,例如体重下降和运动功能受损。
这些结果增加了对PFF模型的渐进性的理解,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.