MOBP and HIP1 in multiple system atrophy: New α-synuclein partners in glial cytoplasmic inclusions implicated in the disease pathogenesis.
MOBP and HIP1 in multiple system atrophy: New α-synuclein partners in glial cytoplasmic inclusions implicated in the disease pathogenesis.
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DOI：
10.1111/nan.12688
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发表时间：
2021-08
影响因子：
5
通讯作者：
Holton JL
中科院分区：
文献类型：
--
作者：
Bettencourt C;Miki Y;Piras IS;de Silva R;Foti SC;Talboom JS;Revesz T;Lashley T;Balazs R;Viré E;Warner TT;Huentelman MJ;Holton JL
多系统萎缩(MSA)是一种致命性神经退行性疾病。与帕金森病类似，海绵状核变性是一种α-突触核仁病，其病理特征是少突胶质细胞中含有α-突触核蛋白的胶质细胞质包涵体。我们先前在MSA中发现髓鞘相关少突胶质细胞碱性蛋白(MOBP)和亨廷顿蛋白相互作用蛋白1(HIP1)DNA甲基化状态的一致变化。我们假设，如果这些基因座上的差异DNA甲基化与MSA有机械上的相关性，那么它应该会对基因调控产生下游影响。我们研究了MSA和健康对照组小脑白质中MOBP和HIP1DNA甲基化与mRNA水平的关系。此外，我们通过蛋白印迹、免疫组织化学和邻近连接分析来分析蛋白质的表达。我们发现，在MSA中，MOBP mRNA水平的降低与DNA甲基化的增加显著相关。对于HIP1，我们发现与健康对照组相比，MSA中DNA甲基化和基因表达水平之间存在明显的关系，这表明该基因可能在MSA中受到表观遗传重塑。虽然小脑白质中MOBP和HIP1的可溶性蛋白水平在MSA患者和对照组之间没有显著差异，但我们发现MSA与其他神经退行性疾病，包括帕金森病和亨廷顿病有显著差异。我们还发现MOBP和HIP1错误地定位在MSA的GCIS中，在那里它们似乎与SNCA相互作用。本研究支持DNA甲基化在MSA中MOBP mRNA下调中的作用。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。通过研究在多系统萎缩中显示显著甲基化改变的基因座，本研究确定髓鞘相关的少突胶质细胞碱性蛋白和亨廷顿蛋白相互作用蛋白1是胶质细胞质内含物(以b和d中的箭头突出显示)和α-突触核蛋白相互作用的新成分，从而加强了这两个基因座在多系统萎缩发病机制中的潜在作用。
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. By investigating loci that have shown significant DNA methylation alterations in multiple system atrophy (MSA), this study identified myelin‐associated oligodendrocyte basic protein (MOBP) and huntingtin interacting protein 1 (HIP1) as new constituents of glial cytoplasmic inclusions (highlighted by arrowheads in b and d) and α‐synuclein interactors, thus strengthening the potential role of these two loci in MSA pathogenesis.
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影响因子：
25
作者：
Lunnon, Katie;Smith, Rebecca;Hannon, Eilis;De Jager, Philip L.;Srivastava, Gyan;Volta, Manuela;Troakes, Claire;Al-Sarraj, Safa;Burrage, Joe;Macdonald, Ruby;Condliffe, Daniel;Harries, Lorna W.;Katsel, Pavel;Haroutunian, Vahram;Kaminsky, Zachary;Joachim, Catharine;Powell, John;Lovestone, Simon;Bennett, David A.;Schalkwyk, Leonard C.;Mill, Jonathan
通讯作者：
Mill, Jonathan
影响因子：
12.3
作者：
Lou S;Lee HM;Qin H;Li JW;Gao Z;Liu X;Chan LL;Kl Lam V;So WY;Wang Y;Lok S;Wang J;Ma RC;Tsui SK;Chan JC;Chan TF;Yip KY
通讯作者：
Yip KY
影响因子：
3.5
作者：
Bianchi, Marzia;Giacomini, Elisa;Magnani, Mauro
通讯作者：
Magnani, Mauro
影响因子：
11.2
作者：
Bradley, Sarah V.;Holland, Eric C.;Ross, Theodora S.
通讯作者：
Ross, Theodora S.
进行性核上麻痹危险基因座的基因表达，甲基化和神经病理相关性。
影响因子：
12.7
作者：
Allen M;Burgess JD;Ballard T;Serie D;Wang X;Younkin CS;Sun Z;Kouri N;Baheti S;Wang C;Carrasquillo MM;Nguyen T;Lincoln S;Malphrus K;Murray M;Golde TE;Price ND;Younkin SG;Schellenberg GD;Asmann Y;Ordog T;Crook J;Dickson D;Ertekin-Taner N
通讯作者：
Ertekin-Taner N