Epigenetic and Metabolic Landscape of Dementia with Lewy Bodies

IF 7.4 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders Pub Date : 2024-12-30 DOI:10.1002/mds.30095

Sangeetha Vishweswaraiah PhD, Ali Yilmaz PhD, Juozas Gordevicius PhD, Milda Milčiūtė PhD, Karolis Krinickis PhD, Ieva Kerseviciute PhD, Bernadette McGuinness PhD, Peter Passmore MD, Patrick G. Kehoe PhD, Brian D. Green PhD, Uppala Radhakrishna PhD, Stewart F. Graham PhD

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Abstract

Background

Lewy body diseases, including dementia with Lewy bodies (DLB), are characterized by α-synuclein accumulation, leading to dementia. Previous studies suggest distinct epigenetic and metabolomic profiles in DLB.

Objective

This study aims to identify diagnostic biomarkers by analyzing the methylome and metabolome in the Brodmann area 7 of postmortem brain tissues from DLB patients and control subjects using multiomics approaches.

Methods

Methylation analysis was performed using the Illumina EPIC array, and metabolomics profiling was conducted via ¹H nuclear magnetic resonance (NMR) and direct injection/liquid chromatography coupled with mass spectrometry. Differential methylation and metabolite analysis were conducted, followed by pathway enrichment to explore biological relevance.

Results

We identified 3478 significantly differentially methylated cytosines, mostly hypermethylated, enriched in CpG islands near transcription start sites. Pathway enrichment analysis showed significant pathways, primarily linked to olfactory and synaptic functions. Metabolomics profiling identified 15 significantly altered metabolites, with Phosphatidylethanolamine (PE) Biosynthesis being the most affected pathway. Key correlations between differentially methylated cytosines and metabolites, particularly in the PE Biosynthesis pathway involving PTDSS1 and PCYT2 genes, were observed.

Conclusions

Notably, sex-specific differences were found, with females exhibiting more epigenetic and metabolomic changes than males. Increased hypermethylation, linked to transcriptional silencing, and disruptions in PE biosynthesis suggest a role in synaptic dysfunction and olfactory deficits. In addition, α-aminoadipic acid was strongly associated with vascular functions, hinting at a possible overlap between vascular health and DLB. This study provides new insights into DLB mechanisms and potential therapeutic targets. © 2024 International Parkinson and Movement Disorder Society.

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路易体痴呆的表观遗传和代谢景观

背景路易体疾病，包括路易体痴呆（DLB），以α‐突触核蛋白积累为特征，导致痴呆。先前的研究表明，DLB具有不同的表观遗传和代谢组学特征。目的利用多组学方法分析DLB患者和对照组死后脑组织Brodmann区7的甲基组和代谢组，以确定诊断性生物标志物。方法采用Illumina EPIC阵列进行甲基化分析，采用1H核磁共振（NMR）和直接注射/液相色谱-质谱联用技术进行代谢组学分析。进行差异甲基化和代谢物分析，然后进行途径富集以探索生物学相关性。结果我们鉴定出3478个显著差异甲基化的胞嘧啶，大多数是高甲基化的，富集在转录起始位点附近的CpG岛。通路富集分析显示了重要的通路，主要与嗅觉和突触功能有关。代谢组学分析鉴定了15种显著改变的代谢物，其中磷脂酰乙醇胺（PE）生物合成是受影响最大的途径。我们观察到不同甲基化的胞嘧啶和代谢物之间的关键相关性，特别是在涉及PTDSS1和PCYT2基因的PE生物合成途径中。值得注意的是，性别特异性差异被发现，女性比男性表现出更多的表观遗传和代谢组学变化。与转录沉默相关的高甲基化增加以及PE生物合成的中断表明其在突触功能障碍和嗅觉缺陷中起作用。此外，α‐氨基己二酸与血管功能密切相关，暗示血管健康与DLB之间可能存在重叠。这项研究为DLB的机制和潜在的治疗靶点提供了新的见解。©2024国际帕金森和运动障碍学会。

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来源期刊

Movement Disorders 医学-临床神经学

CiteScore

13.30

自引率

8.10%

发文量

371

审稿时长

12 months

期刊介绍： Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.