Dementia with lewy bodies patients with high tau levels display unique proteome profiles

IF 14.9 1区 医学 Q1 NEUROSCIENCES Molecular Neurodegeneration Pub Date : 2024-12-19 DOI:10.1186/s13024-024-00782-0
Sinead Greally, Mukesh Kumar, Christoph Schlaffner, Hanne van der Heijden, Elisabeth S. Lawton, Deeptarup Biswas, Sabina Berretta, Hanno Steen, Judith A. Steen
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Abstract

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.
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高tau蛋白水平的路易体痴呆患者表现出独特的蛋白质组谱
临床研究长期以来观察到,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,还存在重叠,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,其症状与阿尔茨海默病(阿尔茨海默病)相似。虽然在DLB中观察到tau病理,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为DLB的受试者(n = 30)和年龄匹配的对照组(n = 29)大脑皮质组织中不溶性部分的蛋白质丰度。使用tau丰度,我们将DLB受试者分为DLBTau+(高丰度)和DLBTau−(低丰度)两个亚组。我们通过蛋白质组学分析,对tau升高的DLB患者的皮层蛋白质组进行表征和比较,并对tau和α-synuclein的分子修饰进行分析,探讨这些患者tau和α-synuclein病理之间的动态关系。蛋白质组学分析显示,与对照组相比,DLBTau+和DLBTau−受试者中存在明显的整体蛋白质失调。值得注意的是,DLBTau+患者表现出tau水平升高,以及泛素和APOE水平升高,表明皮层蛋白质组改变与tau升高相关。比较DLBTau+和DLBTau -组,我们发现DLBTau -组患者的细胞因子信号和代谢途径显著上调,而DLBTau+组患者的蛋白泛素化过程和囊泡介导的运输调节增加。此外,我们还检测了tau蛋白和α-突触核蛋白的翻译后修饰模式。我们的分析显示,两组之间α-突触核蛋白的磷酸化和泛素化位点不同。此外,我们观察到DLBTau+亚群中tau特异性修饰增加。这一分子水平的数据支持了神经退行性疾病作为与AD相比具有不同PTM谱的DLBTau+和DLBTau -患者的连续体的观点。这些发现进一步强调了确定针对神经退行性疾病谱系中所涉及的蛋白质病变的特异性和量身定制的治疗方法的重要性。
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来源期刊
Molecular Neurodegeneration
Molecular Neurodegeneration 医学-神经科学
CiteScore
23.00
自引率
4.60%
发文量
78
审稿时长
6-12 weeks
期刊介绍: Molecular Neurodegeneration, an open-access, peer-reviewed journal, comprehensively covers neurodegeneration research at the molecular and cellular levels. Neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and prion diseases, fall under its purview. These disorders, often linked to advanced aging and characterized by varying degrees of dementia, pose a significant public health concern with the growing aging population. Recent strides in understanding the molecular and cellular mechanisms of these neurodegenerative disorders offer valuable insights into their pathogenesis.
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