Synucleinopathies are neurodegenerative diseases characterized by the accumulation of either neuronal/axonal or glial insoluble proteinaceous aggregates mainly composed of α‐synuclein (α‐syn). Among them, the most common disorders are Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and some forms of familial parkinsonism. Both α‐syn fibrils and oligomers have been found to exert toxic effects on neurons or oligodendroglial cells, can activate neuroinflammatory responses, and mediate the spreading of α‐syn pathology. This poses the question of which is the most toxic α‐syn species. What is worst, α‐syn appears as a very peculiar protein, exerting multiple physiological functions in neurons, especially at synapses, but without acquiring a stable tertiary structure. Its conformation is particularly plastic, and the protein can exist in a natively unfolded state (mainly in solution), partially α‐helical folded state (when it interacts with biological membranes), or oligomeric state (tetramers or dimers with debated functional profile). The extent of α‐syn expression impinges on the resilience of neuronal cells, as multiplications of its gene locus, or overexpression, can cause neurodegeneration and onset of motor phenotype. For these reasons, one of the main challenges in the field of synucleinopathies, which still nowadays can only be managed by symptomatic therapies, has been the development of strategies aimed at reducing α‐syn levels, oligomer formation, fibrillation, or cell‐to‐cell transmission. This review resumes the therapeutic approaches that have been proposed or are under development to counteract α‐syn pathology by direct targeting of this protein and discuss their pros and cons in relation to the current state‐of‐the‐art α‐syn biology.

中文翻译：

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直接针对 α-突触核蛋白的治疗策略的好与坏

突触核蛋白病是神经退行性疾病，其特征在于主要由 α-突触核蛋白 (α-syn) 组成的神经元/轴突或神经胶质不溶性蛋白质聚集体的积累。其中，最常见的疾病是帕金森病、路易体痴呆、多系统萎缩和某些形式的家族性帕金森病。已经发现 α-syn 原纤维和寡聚体对神经元或少突胶质细胞产生毒性作用，可以激活神经炎症反应，并介导 α-syn 病理学的传播。这就提出了哪个是毒性最大的 α-syn 物种的问题。更糟糕的是，α-syn 是一种非常奇特的蛋白质，在神经元中发挥多种生理功能，尤其是在突触处，但没有获得稳定的三级结构。它的构造特别具有塑料感，并且该蛋白质可以以天然未折叠状态（主要在溶液中）、部分 α-螺旋折叠状态（当它与生物膜相互作用时）或寡聚状态（具有有争议的功能特征的四聚体或二聚体）存在。α-syn 表达的程度会影响神经元细胞的弹性，因为其基因座的增殖或过度表达会导致神经变性和运动表型的出现。由于这些原因，突触核蛋白病领域的主要挑战之一是开发旨在降低 α-syn 水平、寡聚体形成、纤颤或细胞对细胞传播。