Aggregation of the protein α‐synuclein (α‐syn) into insoluble intracellular assemblies termed Lewy bodies (LBs) is thought to be a critical pathogenic event in LB diseases such as Parkinson’s disease and dementia with LBs. In LB diseases, the majority of α‐syn is phosphorylated at serine 129 (pS129), suggesting that this is an important disease‐related post‐translational modification (PTM). However, PTMs do not typically occur in isolation and phosphorylation at the proximal tyrosine 125 (pY125) residue has received considerable attention and has been inconsistently reported to be present in LBs. Furthermore, the proximity of Y125 to S129 means that some pS129 antibodies may have epitopes that include Y125, in which case phosphorylation of Y125 will impede recognition of α‐syn. This would potentially lead to underestimating LB pathology burdens if pY125 occurs alongside pS129. To address the apparent controversy in the literature regarding the detection of pY125, we investigated its presence in the LB pathology. We generated pS129 antibodies whose epitope includes or does not include Y125 and compared the extent of α‐syn pathology recognized in mouse models of α‐synucleinopathies, human brain tissue lysates and fixed post‐mortem brain tissues. Our study demonstrated no difference in α‐syn pathology recognized between pS129 antibodies, irrespective of whether Y125 was part of the epitope or not. Furthermore, evaluation with pY125 antibodies whose epitope does not include S129 demonstrated no labeling of LB pathology. This study reconciles disparate results in the literature and demonstrates pY125 is not a key component of LB pathology in murine models or human tissues in idiopathic LB diseases.

中文翻译：

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研究特发性路易氏体病中酪氨酸125和丝氨酸129处双磷酸化α-突触核蛋白的存在。

蛋白α-突触核蛋白（α-syn）聚集到称为路易体（LB）的不溶性细胞内组件中被认为是LB疾病（如帕金森氏病和LB痴呆症）的关键致病事件。在LB疾病中，大多数α-syn在丝氨酸129（pS129）处被磷酸化，表明这是与疾病相关的重要的翻译后修饰（PTM）。但是，PTM通常不会单独发生，近端酪氨酸125（pY125）残基的磷酸化已引起相当大的关注，并不一致地报道了它们在LB中存在。此外，Y125与​​S129的接近性意味着某些pS129抗体可能具有包括Y125的表位，在这种情况下，Y125的磷酸化会阻碍对α-syn的识别。如果pY125与​​pS129一起发生，则可能导致低估LB病理负担。为了解决有关pY125检测的文献中的明显争议，我们调查了其在LB病理学中的存在。我们生成了pS129抗体，其表位包括或不包括Y125，并比较了小鼠α-突触核蛋白病，人脑组织裂解物和固定模型中识别的α-syn病理学程度死后脑组织。我们的研究表明，无论Y125是否为表位的一部分，pS129抗体之间公认的α-syn病理学均无差异。此外，用其表位不包括S129的pY125抗体进行的评估未显示出LB病理的标记。这项研究调和了文献中的不同结果，并证明pY125不是特发性LB疾病的鼠模型或人体组织中LB病理的关键组成部分。