Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK.
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
Neuropathol Appl Neurobiol. 2021 Aug;47(5):640-652. doi: 10.1111/nan.12688. Epub 2021 Jan 19.
Multiple system atrophy (MSA) is a fatal neurodegenerative disease. Similar to Parkinson's disease (PD), MSA is an α-synucleinopathy, and its pathological hallmark consists of glial cytoplasmic inclusions (GCIs) containing α-synuclein (SNCA) in oligodendrocytes. We previously identified consistent changes in myelin-associated oligodendrocyte basic protein (MOBP) and huntingtin interacting protein 1 (HIP1) DNA methylation status in MSA. We hypothesized that if differential DNA methylation at these loci is mechanistically relevant for MSA, it should have downstream consequences on gene regulation.
We investigated the relationship between MOBP and HIP1 DNA methylation and mRNA levels in cerebellar white matter from MSA and healthy controls. Additionally, we analysed protein expression using western blotting, immunohistochemistry and proximity ligation assays.
We found decreased MOBP mRNA levels significantly correlated with increased DNA methylation in MSA. For HIP1, we found a distinct relationship between DNA methylation and gene expression levels in MSA compared to healthy controls, suggesting this locus may be subjected to epigenetic remodelling in MSA. Although soluble protein levels for MOBP and HIP1 in cerebellar white matter were not significantly different between MSA cases and controls, we found striking differences between MSA and other neurodegenerative diseases, including PD and Huntington's disease. We also found that MOBP and HIP1 are mislocalized into the GCIs in MSA, where they appear to interact with SNCA.
This study supports a role for DNA methylation in downregulation of MOBP mRNA in MSA. Most importantly, the identification of MOBP and HIP1 as new constituents of GCIs emphasizes the relevance of these two loci to the pathogenesis of MSA.
多系统萎缩（MSA）是一种致命的神经退行性疾病。与帕金森病（PD）类似，MSA 是一种α-突触核蛋白病，其病理特征是少突胶质细胞质内包涵体（GCIs）中含有α-突触核蛋白（SNCA）。我们之前已经确定了 MSA 中髓鞘相关少突胶质细胞碱性蛋白（MOBP）和亨廷顿相互作用蛋白 1（HIP1）DNA 甲基化状态的一致变化。我们假设，如果这些位点的差异 DNA 甲基化与 MSA 的发病机制有关，那么它应该对基因调控有下游影响。
我们研究了 MSA 和健康对照组小脑白质中 MOBP 和 HIP1 DNA 甲基化与 mRNA 水平之间的关系。此外，我们还使用 Western 印迹、免疫组织化学和接近连接测定分析了蛋白质表达。
我们发现 MSA 中 MOBP mRNA 水平降低与 DNA 甲基化增加显著相关。对于 HIP1，我们发现 MSA 与健康对照组之间 DNA 甲基化与基因表达水平之间存在明显的关系，这表明该基因座可能在 MSA 中受到表观遗传重塑的影响。尽管 MSA 病例和对照组小脑白质中 MOBP 和 HIP1 的可溶性蛋白水平没有显著差异，但我们发现 MSA 与其他神经退行性疾病（包括 PD 和亨廷顿病）之间存在显著差异。我们还发现 MOBP 和 HIP1 在 MSA 中错误定位到 GCIs 中，在那里它们似乎与 SNCA 相互作用。
这项研究支持 DNA 甲基化在 MSA 中下调 MOBP mRNA 的作用。最重要的是，MOBP 和 HIP1 作为 GCIs 的新成分的鉴定强调了这两个基因座与 MSA 发病机制的相关性。
