Transcriptional mutagenesis of α-synuclein caused by DNA oxidation in Parkinson's disease pathogenesis.
Transcriptional mutagenesis of α-synuclein caused by DNA oxidation in Parkinson's disease pathogenesis.
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DOI：
10.1007/s00401-023-02632-7
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发表时间：
2023-11
影响因子：
12.7
通讯作者：
中科院分区：
文献类型：
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作者：
氧化应激在帕金森病（PD）的发展中起着至关重要的作用。 8-oxo-7,8-二氢鸟嘌呤（8-oxodG，氧化鸟嘌呤）是最丰富的氧化应激介导的 DNA 损伤。然而，其在 PD 发病机制中的作用仍不清楚。在这项研究中，我们假设 8-oxodG 可以通过一种称为转录诱变 (TM) 的现象产生具有改变病理聚集的新型 α-突触核蛋白 (α-SYN) 突变体。我们观察到，与年龄匹配的对照相比，PD 患者的中脑基因组 DNA 中 8-oxodG 的积累显着更高，无论是在全球范围内还是在特定于 α-SYN 的区域内。计算机分析预测，43 个氨基酸位置可能导致 TM 衍生的 α-SYN 突变。在这里，我们使用敏感的基于 PCR 的技术报告了与对照组相比，PD 患者中脑中 TM 衍生的 α-SYN 突变体的负载量显着更高。我们发现一种新的丝氨酸42酪氨酸 (S42Y) α-SYN 作为最常检测到的 TM 突变体，顺便说一句，它在所有 TM 变体中具有最高的预测聚合分数。使用新鉴定的 S42Y 抗体对 PD 患者的中脑切片进行免疫组织化学分析，鉴定出负载 S42Y 的路易体 (LB)。我们通过基于细胞和重组蛋白的测定进一步证明，S42Y TM 变体可显着加速 WT α-SYN 聚集。冷冻电子断层扫描显示，与 WT 原纤维相比，S42Y 表现出相当大的构象异质性。此外，与 WT α-SYN 相比，S42Y 表现出更高的神经毒性，如小鼠原代皮质培养物和 C57BL/6 J 小鼠黑质中 AAV 介导的过度表达所示。据我们所知，这是第一份描述 TM 产生的 α-SYN 突变对 LB 形成和 PD 发病机制的可能贡献的报告。在线版本包含可在 10.1007/s00401-023-02632-7 获取的补充材料。
Oxidative stress plays an essential role in the development of Parkinson’s disease (PD). 8-oxo-7,8-dihydroguanine (8-oxodG, oxidized guanine) is the most abundant oxidative stress-mediated DNA lesion. However, its contributing role in underlying PD pathogenesis remains unknown. In this study, we hypothesized that 8-oxodG can generate novel α-synuclein (α-SYN) mutants with altered pathologic aggregation through a phenomenon called transcriptional mutagenesis (TM). We observed a significantly higher accumulation of 8-oxodG in the midbrain genomic DNA from PD patients compared to age-matched controls, both globally and region specifically to α-SYN. In-silico analysis predicted that forty-three amino acid positions can contribute to TM-derived α-SYN mutation. Here, we report a significantly higher load of TM-derived α-SYN mutants from the midbrain of PD patients compared to controls using a sensitive PCR-based technique. We found a novel Serine42Tyrosine (S42Y) α-SYN as the most frequently detected TM mutant, which incidentally had the highest predicted aggregation score amongst all TM variants. Immunohistochemistry of midbrain sections from PD patients using a newly characterized antibody for S42Y identified S42Y-laden Lewy bodies (LB). We further demonstrated that the S42Y TM variant significantly accelerates WT α-SYN aggregation by cell and recombinant protein-based assays. Cryo-electron tomography revealed that S42Y exhibits considerable conformational heterogeneity compared to WT fibrils. Moreover, S42Y exhibited higher neurotoxicity compared to WT α-SYN as shown in mouse primary cortical cultures and AAV-mediated overexpression in the substantia nigra of C57BL/6 J mice. To our knowledge, this is the first report describing the possible contribution of TM-generated mutations of α-SYN to LB formation and PD pathogenesis. The online version contains supplementary material available at 10.1007/s00401-023-02632-7.
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影响因子：
17.1
作者：
Di Maio R;Barrett PJ;Hoffman EK;Barrett CW;Zharikov A;Borah A;Hu X;McCoy J;Chu CT;Burton EA;Hastings TG;Greenamyre JT
通讯作者：
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DOI：
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发表时间：
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影响因子：
11.1
作者：
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通讯作者：
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影响因子：
4.7
作者：
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通讯作者：
Halliwell, B
DOI：
10.1073/pnas.2210038120
发表时间：
2023-01-31
影响因子：
11.1
作者：
Chung, Claire;Verheijen, Bert M.;Zhang, Xinmin;Huang, Biao;Coakley, Aeowynn;McGann, Eric;Wade, Emily;Dinep-Schneider, Olivia;LaGosh, Jessica;Anagnostou, Maria-Eleni;Simpson, Stephen;Thomas, Kelly;Ernst, Mimi;Rattray, Allison;Lynch, Michael;Kashlev, Mikhail;Benayoun, Berenice A.;Li, Zhongwei;Strathern, Jeffrey;Gout, Jean-Francois;Vermulst, Marc
通讯作者：
Vermulst, Marc