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Abstract：
Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by neuronal loss and gliosis, with oligodendroglial cytoplasmic inclusions (GCIs) containing α-synuclein being the primary pathological hallmark. Clinical presentations of MSA overlap with other parkinsonian disorders, such as Parkinson\'s disease (PD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP), posing challenges in early diagnosis. Numerous studies have reported alterations in DNA methylation in neurodegenerative diseases, with candidate loci being identified in various parkinsonian disorders including MSA, PD, and PSP. Although MSA and PSP present with substantial white matter pathology, alterations in white matter have also been reported in PD. However, studies comparing the DNA methylation architectures of white matter in these diseases are lacking. We therefore aimed to investigate genome-wide DNA methylation patterns in the frontal lobe white matter of individuals with MSA (n = 17), PD (n = 17), and PSP (n = 16) along with controls (n = 15) using the Illumina EPIC array, to identify shared and disease-specific DNA methylation alterations. Genome-wide DNA methylation profiling of frontal lobe white matter in the three parkinsonian disorders revealed substantial commonalities in DNA methylation alterations in MSA, PD, and PSP. We further used weighted gene correlation network analysis to identify disease-associated co-methylation signatures and identified dysregulation in processes relating to Wnt signaling, signal transduction, endoplasmic reticulum stress, mitochondrial processes, RNA interference, and endosomal transport to be shared between these parkinsonian disorders. Our overall analysis points toward more similarities in DNA methylation patterns between MSA and PD, both synucleinopathies, compared to that between MSA and PD with PSP, which is a tauopathy. Our results also highlight several shared DNA methylation changes and pathways indicative of converging molecular mechanisms in the white matter contributing toward neurodegeneration in all three parkinsonian disorders.
摘要：
多系统萎缩（MSA）是一种罕见的神经退行性疾病，以神经元丢失和神经胶质增生为特征，含有α-突触核蛋白的少突胶质细胞质内含物（GCI）是主要的病理标志。MSA的临床表现与其他帕金森病重叠，如帕金森病（PD），路易体痴呆（DLB），和进行性核上性麻痹（PSP），对早期诊断提出挑战。大量研究报道了神经退行性疾病中DNA甲基化的改变，在包括MSA在内的各种帕金森病中鉴定出候选基因座，PD,和PSP。尽管MSA和PSP存在大量的白质病理，在PD中也有白质改变的报道。然而,缺乏比较这些疾病中白质DNA甲基化结构的研究。因此，我们旨在研究MSA患者额叶白质的全基因组DNA甲基化模式（n=17），PD（n=17），和PSP（n=16）以及使用IlluminaEPIC阵列的控件（n=15），鉴定共有和疾病特异性DNA甲基化改变。三种帕金森病患者额叶白质的全基因组DNA甲基化分析揭示了MSA中DNA甲基化改变的实质性共性。PD,和PSP。我们进一步使用加权基因相关网络分析来鉴定疾病相关的共甲基化特征，并鉴定与Wnt信号相关的过程中的失调。信号转导，内质网应激,线粒体过程，RNA干扰,和内体运输在这些帕金森病之间共享。我们的总体分析指出，MSA和PD之间的DNA甲基化模式更相似，两种突触核蛋白病，与PSP的MSA和PD相比，这是一种tau蛋白病。我们的结果还强调了几种共享的DNA甲基化变化和通路，表明白质中的趋同分子机制有助于所有三种帕金森病中的神经变性。
