α-突触核蛋白过表达诱导谷氨酸信号和运动通路的表观基因组失调。

Alpha-synuclein overexpression induces epigenomic dysregulation of glutamate signaling and locomotor pathways.

机构信息

Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.

Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, 37073 Göttingen, Germany.

出版信息

Hum Mol Genet. 2022 Oct 28;31(21):3694-3714. doi: 10.1093/hmg/ddac104.

Parkinson's disease (PD) is a neurological disorder with complex interindividual etiology that is becoming increasingly prevalent worldwide. Elevated alpha-synuclein levels can increase risk of PD and may influence epigenetic regulation of PD pathways. Here, we report genome-wide DNA methylation and hydroxymethylation alterations associated with overexpression of two PD-linked alpha-synuclein variants (wild-type and A30P) in LUHMES cells differentiated to dopaminergic neurons. Alpha-synuclein altered DNA methylation at thousands of CpGs and DNA hydroxymethylation at hundreds of CpGs in both genotypes, primarily in locomotor behavior and glutamate signaling pathway genes. In some cases, epigenetic changes were associated with transcription. SMITE network analysis incorporating H3K4me1 ChIP-seq to score DNA methylation and hydroxymethylation changes across promoters, enhancers, and gene bodies confirmed epigenetic and transcriptional deregulation of glutamate signaling modules in both genotypes. Our results identify distinct and shared impacts of alpha-synuclein variants on the epigenome, and associate alpha-synuclein with the epigenetic etiology of PD.

帕金森病（PD）是一种具有复杂个体间病因的神经退行性疾病，在全球范围内的发病率越来越高。α-突触核蛋白水平升高会增加 PD 的风险，并可能影响 PD 通路的表观遗传调控。在这里，我们报告了与 LUHMES 细胞向多巴胺能神经元分化过程中过表达两种与 PD 相关的 α-突触核蛋白变异体（野生型和 A30P）相关的全基因组 DNA 甲基化和羟甲基化改变。α-突触核蛋白改变了两种基因型中数千个 CpG 位点的 DNA 甲基化和数百个 CpG 位点的 DNA 羟甲基化，主要影响运动行为和谷氨酸信号通路基因。在某些情况下，表观遗传变化与转录有关。SMITE 网络分析结合 H3K4me1 ChIP-seq 对启动子、增强子和基因体上的 DNA 甲基化和羟甲基化变化进行评分，证实了两种基因型中谷氨酸信号模块的表观遗传和转录失调。我们的研究结果确定了 α-突触核蛋白变异体对表观基因组的独特和共同影响，并将 α-突触核蛋白与 PD 的表观遗传病因联系起来。