Bridi Jessika C, Bereczki Erika, Smith Saffron K, Poças Gonçalo M, Kottler Benjamin, Domingos Pedro M, Elliott Christopher J, Aarsland Dag, Hirth Frank
Department of Basic & Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London SE5 9RX, UK.
Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Novum, Stockholm 171 77, Sweden.
Brain Commun. 2021 Mar 22;3(2):fcab049. doi: 10.1093/braincomms/fcab049. eCollection 2021.
Alpha-synuclein (α-syn) mislocalization and accumulation in intracellular inclusions is the major pathological hallmark of degenerative synucleinopathies, including Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies. Typical symptoms are behavioural abnormalities including motor deficits that mark disease progression, while non-motor symptoms and synaptic deficits are already apparent during the early stages of disease. Synucleinopathies have therefore been considered synaptopathies that exhibit synaptic dysfunction prior to neurodegeneration. However, the mechanisms and events underlying synaptopathy are largely unknown. Here we investigated the cascade of pathological events underlying α-syn accumulation and toxicity in a model of synucleinopathy by employing a combination of histological, biochemical, behavioural and electrophysiological assays. Our findings demonstrate that targeted expression of human α-syn leads to its accumulation in presynaptic terminals that caused downregulation of synaptic proteins, cysteine string protein, synapsin, and syntaxin 1A, and a reduction in the number of Bruchpilot puncta, the core component of the presynaptic active zone essential for its structural integrity and function. These α-syn-mediated presynaptic alterations resulted in impaired neuronal function, which triggered behavioural deficits in ageing that occurred prior to progressive degeneration of dopaminergic neurons. Comparable alterations in presynaptic active zone protein were found in patient brain samples of dementia with Lewy bodies. Together, these findings demonstrate that presynaptic accumulation of α-syn impairs the active zone and neuronal function, which together cause synaptopathy that results in behavioural deficits and the progressive loss of dopaminergic neurons. This sequence of events resembles the cytological and behavioural phenotypes that characterise the onset and progression of synucleinopathies, suggesting that α-syn-mediated synaptopathy is an initiating cause of age-related neurodegeneration.
α-突触核蛋白（α-syn）在细胞内包涵体中的错误定位和积累是包括帕金森病、帕金森病痴呆和路易体痴呆在内的退行性突触核蛋白病的主要病理标志。典型症状是行为异常，包括标志疾病进展的运动缺陷，而非运动症状和突触缺陷在疾病早期就已明显。因此，突触核蛋白病被认为是在神经退行性变之前就表现出突触功能障碍的突触病。然而，突触病背后的机制和事件在很大程度上尚不清楚。在这里，我们通过结合组织学、生物化学、行为学和电生理学分析，研究了突触核蛋白病模型中α-syn积累和毒性背后的一系列病理事件。我们的研究结果表明，人α-syn的靶向表达导致其在突触前终末积累，从而引起突触蛋白、半胱氨酸串珠蛋白、突触素和 syntaxin 1A的下调，以及Bruchpilot 斑点数量的减少，Bruchpilot斑点是突触前活性区的核心成分，对其结构完整性和功能至关重要。这些α-syn介导的突触前改变导致神经元功能受损，进而引发衰老过程中的行为缺陷，这发生在多巴胺能神经元进行性退变之前。在路易体痴呆患者的脑样本中发现了突触前活性区蛋白的类似改变。总之，这些发现表明α-syn在突触前的积累损害了活性区和神经元功能，共同导致突触病，进而导致行为缺陷和多巴胺能神经元的逐渐丧失。这一系列事件类似于表征突触核蛋白病发生和进展的细胞学和行为学表型，表明α-syn介导的突触病是与年龄相关的神经退行性变的起始原因。
