Clinical studies have long observed that neurodegenerative disorders display a range of symptoms and pathological features and, in some cases, overlap, suggesting that these diseases exist on a spectrum. Dementia with Lewy Bodies (DLB), a synucleinopathy, is a prominent example, where symptomatic similarities with tauopathy, Alzheimer’s disease, are observed. Although tau pathology has been observed in DLB, the interplay between tau and α-synuclein is poorly understood at a molecular level. Quantitative mass spectrometry analysis was used to measure protein abundance in the insoluble fraction from cortical brain tissue from pathologically diagnosed DLB subjects (n = 30) and age-matched controls (n = 29). Using tau abundance, we stratified the DLB subjects into two subgroups termed DLBTau+ (higher abundance) and DLBTau− (lower abundance). We conducted proteomic analysis to characterize and compare the cortical proteome of DLB subjects exhibiting elevated tau, as well as the molecular modifications of tau and α-synuclein to explore the dynamic between tau and α-synuclein pathology in these patients. Proteomic analyses revealed distinct global protein dysregulations in DLBTau+ and DLBTau− subjects when compared to controls. Notably, DLBTau+ patients exhibited increased levels of tau, along with ubiquitin, and APOE, indicative of cortical proteome alterations associated with elevated tau. Comparing DLBTau+ and DLBTau− groups, we observed significant upregulation of cytokine signaling and metabolic pathways in DLBTau− patients, while DLBTau+ subjects showed increases in protein ubiquitination processes and regulation of vesicle-mediated transport. Additionally, we examined the post-translational modification patterns of tau and α-synuclein. Our analysis revealed distinct phosphorylation and ubiquitination sites on α-synuclein between groups. Moreover, we observed increased modifications on tau specifically within the DLBTau+ subgroup. This molecular-level data supports the idea of neurodegenerative disease as a continuum of diseases with distinct PTM profiles DLBTau+ and DLBTau− patients in comparison to AD. These findings further emphasize the importance of identifying specific and tailored therapeutic approaches targeting the involved proteopathies in the neurodegenerative disease spectrum.

中文翻译：

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路易体痴呆 高 tau 水平的患者表现出独特的蛋白质组谱


临床研究长期以来一直观察到，神经退行性疾病表现出一系列症状和病理特征，在某些情况下，还会重叠，这表明这些疾病存在于一个谱系中。路易体痴呆 （DLB） 是一种突触核蛋白病，是一个突出的例子，其中观察到症状与 tau 病、阿尔茨海默病的相似性。尽管在 DLB 中观察到 tau 病理学，但在分子水平上对 tau 和 α-突触核蛋白之间的相互作用知之甚少。定量质谱分析用于测量病理诊断的 DLB 受试者 （n = 30） 和年龄匹配的对照 （n = 29） 的皮质脑组织不溶性部分中的蛋白质丰度。使用 tau 丰度，我们将 DLB 受试者分为两个亚组，称为 DLBTau + （较高丰度）和 DLBTau - （较低丰度）。我们进行了蛋白质组学分析，以表征和比较表现出 tau 升高的 DLB 受试者的皮质蛋白质组，以及 tau 和 α-突触核蛋白的分子修饰，以探索这些患者 tau 和 α-突触核蛋白病理之间的动态。蛋白质组学分析显示，与对照组相比，DLBTau+ 和 DLBTau− 受试者具有不同的整体蛋白质失调。值得注意的是，DLBTau+ 患者表现出 tau 水平升高，以及泛素和 APOE，表明与 tau 升高相关的皮质蛋白质组改变。比较 DLBTau + 和 DLBTau - 组，我们观察到 DLBTau - 患者细胞因子信号传导和代谢途径显著上调，而 DLBTau + 受试者表现出蛋白质泛素化过程和囊泡介导转运调节的增加。此外，我们检查了 tau 和 α-突触核蛋白的翻译后修饰模式。 我们的分析揭示了组间 α-突触核蛋白上不同的磷酸化和泛素化位点。此外，我们观察到 DLBTau+ 亚组内 tau 修饰增加。该分子水平数据支持神经退行性疾病的观点，即与 AD 患者相比，神经退行性疾病是具有不同 PTM 特征的疾病连续体 DLBTau+ 和 DLBTau− 患者。这些发现进一步强调了确定针对神经退行性疾病谱中受累蛋白病的特异性和定制治疗方法的重要性。