The two main pathological hallmarks of Parkinson's disease are loss of dopamine neurons in the substantia nigra pars compacta and proteinaceous amyloid fibrils composed mostly of α-synuclein, called Lewy pathology. Levodopa to enhance dopaminergic transmission remains one of the most effective treatment for alleviating the motor symptoms of Parkinson's disease (Olanow, Mov Disord 34:812-815, 2019). In addition, deep brain stimulation (Bronstein et al., Arch Neurol 68:165, 2011) to modulate basal ganglia circuit activity successfully alleviates some motor symptoms. MRI guided focused ultrasound in the subthalamic nucleus is a promising therapeutic strategy as well (Martinez-Fernandez et al., Lancet Neurol 17:54-63, 2018). However, to date, there exists no treatment that stops the progression of this disease. The findings that α-synuclein can be released from neurons and inherited through interconnected neural networks opened the door for discovering novel treatment strategies to prevent the formation and spread of Lewy pathology with the goal of halting PD in its tracks. This hypothesis is based on discoveries that pathologic aggregates of α-synuclein induce the endogenous α-synuclein protein to adopt a similar pathologic conformation, and is thus self-propagating. Phase I clinical trials are currently ongoing to test treatments such as immunotherapy to prevent the neuron to neuron spread of extracellular aggregates. Although tremendous progress has been made in understanding how Lewy pathology forms and spreads throughout the brain, cell intrinsic factors also play a critical role in the formation of pathologic α-synuclein, such as mechanisms that increase endogenous α-synuclein levels, selective expression profiles in distinct neuron subtypes, mutations and altered function of proteins involved in α-synuclein synthesis and degradation, and oxidative stress. Strategies that prevent the formation of pathologic α-synuclein should consider extracellular release and propagation, as well as neuron intrinsic mechanisms.

中文翻译：

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α-突触核蛋白聚集在神经系统中的起始和传播。

帕金森氏病的两个主要病理标志是黑质致密部中的多巴胺神经元丢失和主要由α-突触核蛋白组成的蛋白质性淀粉样原纤维，称为路易氏病理学。左旋多巴增强多巴胺能传递仍然是减轻帕金森氏病运动症状的最有效方法之一（Olanow，Mov Disord 34：812-815，2019）。另外，深度脑刺激（Bronstein等人，Arch Neurol 68：165，2011）调节基底神经节回路活动成功地减轻了一些运动症状。MRI引导下丘脑核内聚焦超声也是一种有前途的治疗策略（Martinez-Fernandez等，Lancet Neurol 17：54-63，2018）。然而，迄今为止，还没有治疗可以阻止这种疾病的发展。α-突触核蛋白可以从神经元中释放并通过相互连接的神经网络继承的发现，为发现新的治疗策略以防止路易氏病的形成和扩散打开了大门，其目的是将PD停在其轨迹中。该假设基于以下发现：α-突触核蛋白的病理聚集体诱导内源性α-突触核蛋白蛋白采取相似的病理构象，因此是自我繁殖的。目前正在进行I期临床试验，以测试诸如免疫疗法等治疗方法，以防止神经元向神经元扩散到细胞外聚集物中。尽管在了解路易氏病理学如何在大脑中形成和扩散方面已经取得了巨大进展，但是细胞内在因素在病理性α-突触核蛋白的形成中也起着至关重要的作用，例如增加内源性α-突触核蛋白水平的机制，不同神经元亚型的选择性表达谱，参与α-突触核蛋白合成和降解的蛋白质的突变和功能改变以及氧化应激。防止病理性α-突触核蛋白形成的策略应考虑细胞外释放和繁殖以及神经元内在机制。