The etiology and pathogenesis of Parkinson’s disease (PD) are tightly linked to the gain-of-function of α-synuclein. However, gradual accumulation of α-synuclein aggregates in dopaminergic neurons of substantia nigra pars compacta (SNpc) leads to the depletion of the functional pool of soluble α-synuclein, and therefore, creates loss-of-function conditions, particularly in presynaptic terminals of these neurons. Studies of how this late-onset depletion of a protein involved in many important steps of neurotransmission contributes to PD progression and particularly, to worsening the nigrostriatal pathology at late stages of the disease are limited and obtained data, are controversial. Recently, we produced a mouse line for conditional knockout of the gene encoding α-synuclein, and here we used its tamoxifen-inducible pan-neuronal inactivation to study consequences of the adult-onset (from the age of 6 months) and late-onset (from the age of 12 months) α-synuclein depletion to the nigrostriatal system. No significant changes of animal balance/coordination, the number of dopaminergic neurons in the SNpc and the content of dopamine and its metabolites in the striatum were observed after adult-onset α-synuclein depletion, but in aging (18-month-old) late-onset depleted mice we found a significant reduction of major dopamine metabolites without changes to the content of dopamine itself. Our data suggest that this might be caused, at least partially, by reduced expression of aldehyde dehydrogenase ALDH1a1 and could lead to the accumulation of toxic intermediates of dopamine catabolism. By extrapolating our findings to a potential clinical situation, we suggest that therapeutic downregulation of α-synuclein expression in PD patients is a generally safe option as it should not cause adverse side effects on the functionality of their nigrostriatal system. However, if started in aged patients, this type of therapy might trigger slight functional changes of the nigrostriatal system with potentially unwanted additive effect to already existing pathology.

中文翻译：

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成年和衰老小鼠神经元中 α-突触核蛋白条件失活后黑质纹状体系统的变化


帕金森病 (PD) 的病因和发病机制与 α-突触核蛋白的功能获得密切相关。然而，黑质致密部 (SNpc) 多巴胺能神经元中 α-突触核蛋白聚集体的逐渐积累导致可溶性 α-突触核蛋白功能库的耗尽，因此造成功能丧失，特别是在黑质致密部的突触前末端。这些神经元。参与神经传递许多重要步骤的蛋白质的迟发性耗竭如何导致帕金森病进展，特别是导致疾病晚期黑质纹状体病理恶化的研究有限，并且获得的数据存在争议。最近，我们生产了一个用于条件性敲除编码 α-突触核蛋白的基因的小鼠品系，在这里我们使用其他莫昔芬诱导的全神经元失活来研究成人发病（从 6 个月大）和晚发型的后果（从 12 个月大起）黑质纹状体系统的 α-突触核蛋白耗竭。在成年发病的α-突触核蛋白耗竭后，没有观察到动物平衡/协调、SNpc中多巴胺能神经元的数量以及纹状体中多巴胺及其代谢物的含量的显着变化，但在衰老（18月龄）晚期我们发现，在发病耗竭的小鼠中，主要多巴胺代谢物显着减少，而多巴胺本身的含量没有变化。我们的数据表明，这可能至少部分是由乙醛脱氢酶 ALDH1a1 表达减少引起的，并可能导致多巴胺分解代谢有毒中间体的积累。 通过将我们的研究结果外推到潜在的临床情况，我们建议在 PD 患者中下调 α-突触核蛋白表达的治疗通常是安全的选择，因为它不会对其黑质纹状体系统的功能造成不良副作用。然而，如果在老年患者中开始，这种类型的治疗可能会引发黑质纹状体系统的轻微功能变化，并对现有的病理学产生潜在的不良附加效应。