Reta Lila Weston Institute and Department of Movement Neuroscience, UCL Queen Square Institute of Neurology, 1 Wakefield Street, London WC1N 1PJ, UK.
Department of Neuroscience, Graduate School of Medical Sciences, Weill Cornell Medical College, Cornell University, Ithaca, NY 10065, USA.
Cells. 2022 Mar 6;11(5):906. doi: 10.3390/cells11050906.
Aggregated alpha-synuclein (α-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson's disease (IPD) and multiple system atrophy (MSA). Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of α-synuclein exist, including phosphorylated and nitrated forms. It is unclear which α-synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant α-synuclein PTMs in postmortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three α-synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 IPD cases, 5 MSA cases, and 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 α-synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures, followed by nY39 α-synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 α-synuclein in MSA. Quantification of the LB scores revealed that pS129 α-synuclein was the dominant and earliest α-synuclein PTM, followed by nY39 α-synuclein, while lower amounts of pSer87 α-synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments.
聚集的α-突触核蛋白（α-synuclein）是路易体（Lewy bodies，LB）、路易神经突（Lewy neurites，LN）和神经胶质细胞质包涵体（glial cytoplasmic inclusions，GCI）的主要成分，这些是特发性帕金森病（idiopathic Parkinson's disease，IPD）和多系统萎缩（multiple system atrophy，MSA）的病理学特征。导致形成 LB/LN/GCI 的起始因素仍不清楚。α-突触核蛋白存在几种形式，包括磷酸化和硝化形式。目前尚不清楚哪种 α-突触核蛋白翻译后修饰（post-translational modifications，PTMs）会出现在整个疾病病理学过程中的聚集体中。在此，我们旨在使用免疫组织化学方法确定尸检 IPD 和 MSA 病理学中主要的 α-突触核蛋白 PTM。我们同时检查了 15 例 IPD 病例、5 例 MSA 病例和 6 例神经正常对照的受影响病理学区域中三种 α-突触核蛋白 PTM（pS87、pS129、nY39）的模式。所有抗体均识别 LB、LN 和 GCI，尽管程度不同。pS129 α-突触核蛋白抗体对 LN 和突触点状结构的免疫反应特别强烈，其次是 nY39 α-突触核蛋白抗体。MSA 中的 GCI、神经元包涵体和小纤维对 nY39 α-突触核蛋白呈阳性。LB 评分的定量分析表明，pS129 α-突触核蛋白是主要的和最早的 α-突触核蛋白 PTM，其次是 nY39 α-突触核蛋白，而 pSer87 α-突触核蛋白的含量在 PD 疾病进展中出现得更晚。这些结果可能对新的生物标志物和治疗方法的发展具有重要意义。
