Department of Neurology, Oslo University Hospital, Oslo, Norway.
University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK.
Nat Commun. 2022 Aug 22;13(1):4932. doi: 10.1038/s41467-022-32619-z.
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2, SFMBT2, AKAP6 and PHYHIP. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.
帕金森病（PD）和路易体痴呆（DLB）是两种密切相关的进行性疾病，目前尚无有效的疾病修饰疗法，其神经病理学特征为错误折叠的α-突触核蛋白在神经元内聚集。为了探究 DNA 甲基化变化在 PD 和 DLB 发病机制中的作用，我们对 322 例死后额叶皮质样本进行了全基因组甲基化关联研究（EWAS），并在 200 名独立供体的独立样本中对结果进行了复制。我们报告了与 TMCC2、SFMBT2、AKAP6 和 PHYHIP 附近的 Braak 路易体阶段相关的新型差异甲基化复制位点。差异甲基化探针与已知的 PD 遗传风险等位基因无关。Meta 分析为 PD 相关 22q11.2 缺失所影响的染色体区域内的差异甲基化位点提供了提示性证据。我们的研究结果阐明了 PD 和 DLB 中的新疾病途径，并为路易体病理学的未来分子研究提出了假说。
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