Laboratory of Structural Neuropathology, Doshisha University Graduate School of Brain Science, 1-3 Miyakodanitatara, Kyotanabe-shi, Kyoto, 610-0394, Japan.
Department of Neurology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Commun Biol. 2022 Jun 29;5(1):636. doi: 10.1038/s42003-022-03590-8.
Synucleinopathies are neurodegenerative disorders including Parkinson disease (PD), dementia with Lewy body (DLB), and multiple system atrophy (MSA) that involve deposits of the protein alpha-synuclein (α-syn) in the brain. The inoculation of α-syn aggregates derived from synucleinopathy or preformed fibrils (PFF) formed in vitro induces misfolding and deposition of endogenous α-syn. This is referred to as prion-like transmission, and the mechanism is still unknown. In this study, we label α-syn PFF with quantum dots and visualize their movement directly in acute slices of brain tissue inoculated with α-syn PFF seeds. Using this system, we find that the trafficking of α-syn seeds is dependent on fast axonal transport and the seed spreading is dependent on endocytosis and neuronal activity. We also observe pharmacological effects on α-syn seed spreading; clinically available drugs including riluzole are effective in reducing the spread of α-syn seeds and this effect is also observed in vivo. Our quantum-dot-labeled α-syn seed assay system combined with in vivo transmission experiment reveals an early phase of transmission, in which uptake and spreading of seeds occur depending on neuronal activity, and a later phase, in which seeds induce the propagation of endogenous misfolded α-syn.
突触核蛋白病是一种神经退行性疾病，包括帕金森病（PD）、路易体痴呆（DLB）和多系统萎缩（MSA），这些疾病涉及脑内的蛋白质α-突触核蛋白（α-syn）沉积。接种源自突触核蛋白病的α-syn 聚集物或体外形成的原纤维（PFF）会诱导内源性α-syn 的错误折叠和沉积。这被称为类朊病毒样传播，其机制尚不清楚。在这项研究中，我们用量子点标记α-syn PFF，并直接在接种了α-syn PFF 种子的急性脑组织切片中可视化它们的运动。使用这个系统，我们发现α-syn 种子的运输依赖于快速轴突运输，而种子的扩散依赖于内吞作用和神经元活性。我们还观察到了对α-syn 种子扩散的药理学效应；临床上可用的药物，包括利鲁唑，可有效减少α-syn 种子的扩散，并且这种效应也在体内观察到。我们的量子点标记α-syn 种子检测系统与体内传播实验相结合，揭示了一个早期的传播阶段，在此阶段，种子的摄取和扩散取决于神经元活性，以及一个后期阶段，在此阶段，种子诱导内源性错误折叠的α-syn 的传播。
