It is necessary to develop an understanding of the specific mechanisms involved in alpha-synuclein aggregation and propagation to develop disease modifying therapies for age-related synucleinopathies, including Parkinson’s disease and Dementia with Lewy Bodies. To adequately address this question, we developed a new transgenic mouse model of synucleinopathy that expresses human A53T SynGFP under control of the mouse prion protein promoter. Our characterization of this mouse line demonstrates that it exhibits several distinct advantages over other, currently available, mouse models. This new model allows rigorous study of the initial location of Lewy pathology formation and propagation in the living brain, and strongly suggests that aggregation begins in axonal structures with retrograde propagation to the cell body. This model also shows expeditious development of alpha-synuclein pathology following induction with small, in vitro-generated alpha-synuclein pre-formed fibrils (PFFs), as well as accelerated cell death of inclusion-bearing cells. Using this model, we found that aggregated alpha-synuclein somatic inclusions developed first in neurons, but later showed a second wave of inclusion formation in astrocytes. Interestingly, astrocytes appear to survive much longer after inclusion formation than their neuronal counterparts. This model also allowed careful study of peripheral-to-central spread of Lewy pathology after PFF injection into the hind limb musculature. Our results clearly show evidence of progressive, retrograde trans-synaptic spread of Lewy pathology through known neuroanatomically connected pathways in the motor system. As such, we have developed a promising tool to understand the biology of neurodegeneration associated with alpha-synuclein aggregation and to discover new treatments capable of altering the neurodegenerative disease course of synucleinopathies.

中文翻译：

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在突触核蛋白病体内 A53T α-突触核蛋白小鼠模型中注射预形成原纤维后，路易病理学的跨突触和逆行轴突扩散。


有必要了解 α-突触核蛋白聚集和传播的具体机制，以开发针对年龄相关突触核蛋白病（包括帕金森病和路易体痴呆）的疾病修饰疗法。为了充分解决这个问题，我们开发了一种新的突触核蛋白病转基因小鼠模型，该模型在小鼠朊病毒蛋白启动子的控制下表达人 A53T SynGFP。我们对该小鼠系列的表征表明，与其他现有的小鼠模型相比，它表现出几个明显的优势。这种新模型可以对活体大脑中路易病理形成和传播的初始位置进行严格研究，并强烈表明聚集始于轴突结构，并逆行传播到细胞体。该模型还显示，在体外生成的小 α-突触核蛋白预形成原纤维 (PFF) 诱导后，α-突触核蛋白病理学迅速发展，以及包含包涵体细胞的加速细胞死亡。使用该模型，我们发现聚集的α-突触核蛋白体细胞包涵体首先在神经元中发育，但随后在星形胶质细胞中显示出第二波包涵体形成。有趣的是，星形胶质细胞在包涵体形成后的存活时间似乎比神经元对应物要长得多。该模型还可以仔细研究 PFF 注射到后肢肌肉组织后路易病理学从外周到中央的扩散。我们的结果清楚地表明，路易病理学通过运动系统中已知的神经解剖学连接途径进行渐进、逆行跨突触传播。 因此，我们开发了一种有前景的工具来了解与 α-突触核蛋白聚集相关的神经退行性生物学，并发现能够改变突触核蛋白病的神经退行性疾病进程的新疗法。