Cytosolic dsDNA of mitochondrial origin induces cytotoxicity and neurodegeneration in cellular and zebrafish models of Parkinson's disease.
Cytosolic dsDNA of mitochondrial origin induces cytotoxicity and neurodegeneration in cellular and zebrafish models of Parkinson's disease.
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线粒体起源的胞质DsDNA在帕金森氏病的细胞和斑马鱼模型中诱导细胞毒性和神经退行性。
DOI：
10.1038/s41467-021-23452-x
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发表时间：
2021-05-25
影响因子：
16.6
通讯作者：
Kakita A
中科院分区：
文献类型：
--
作者：
Matsui H;Ito J;Matsui N;Uechi T;Onodera O;Kakita A
线粒体功能障碍和溶酶体功能障碍与帕金森病（PD）有关，但PD发病机制中这些功能障碍之间的联系仍不清楚。在这里，我们报告，从溶酶体降解的线粒体起源的胞质dsDNA逃逸，诱导细胞毒性在培养的细胞和PD表型在体内。PINK 1、GBA和/或ATP 13 A2的消耗导致线粒体来源的胞质dsDNA增加，并诱导培养的细胞系中的I型干扰素（IFN）应答和细胞死亡。这些表型通过DNA酶II（一种降解丢弃的线粒体DNA的溶酶体DNA酶）的过表达或IFI 16（其充当线粒体来源的胞质dsDNA的传感器）的耗尽而被拯救。通过过表达人DNA酶II减少胞质dsDNA的丰度改善gba突变PD模型斑马鱼中的运动障碍和多巴胺能细胞损失。此外，IFI 16和线粒体来源的胞质dsDNA斑点在PD患者的脑中积累。这些结果支持线粒体DNA胞质渗漏在PD发病机制中的共同致病作用。线粒体和溶酶体功能障碍是帕金森病（PD）发病机制的核心。在这里，作者显示了PD的细胞和斑马鱼模型中细胞溶质中的线粒体dsDNA诱导细胞毒性和神经变性; IFI 16（一种细胞溶质dsDNA传感器）的敲低可挽救细胞毒性，溶酶体DNA酶II的过表达也是如此。
Mitochondrial dysfunction and lysosomal dysfunction have been implicated in Parkinson’s disease (PD), but the links between these dysfunctions in PD pathogenesis are still largely unknown. Here we report that cytosolic dsDNA of mitochondrial origin escaping from lysosomal degradation was shown to induce cytotoxicity in cultured cells and PD phenotypes in vivo. The depletion of PINK1, GBA and/or ATP13A2 causes increases in cytosolic dsDNA of mitochondrial origin and induces type I interferon (IFN) responses and cell death in cultured cell lines. These phenotypes are rescued by the overexpression of DNase II, a lysosomal DNase that degrades discarded mitochondrial DNA, or the depletion of IFI16, which acts as a sensor for cytosolic dsDNA of mitochondrial origin. Reducing the abundance of cytosolic dsDNA by overexpressing human DNase II ameliorates movement disorders and dopaminergic cell loss in gba mutant PD model zebrafish. Furthermore, IFI16 and cytosolic dsDNA puncta of mitochondrial origin accumulate in the brain of patients with PD. These results support a common causative role for the cytosolic leakage of mitochondrial DNA in PD pathogenesis. Mitochondrial and lysosomal dysfunction are central to Parkinson’s disease (PD) pathogenesis. Here, the authors show mitochondrial dsDNA in the cytosol in cellular and Zebrafish models of PD induces cytotoxicity and neurodegeneration; knock-down of IFI16, a cytosolic dsDNA sensor, rescues cytotoxicity, as does overexpression of lysosomal DNAse II.
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影响因子：
56.9
作者：
Kawane, K;Fukuyama, H;Nagata, S
通讯作者：
Nagata, S
影响因子：
64.8
作者：
Oka, Takafumi;Hikoso, Shungo;Yamaguchi, Osamu;Taneike, Manabu;Takeda, Toshihiro;Tamai, Takahito;Oyabu, Jota;Murakawa, Tomokazu;Nakayama, Hiroyuki;Nishida, Kazuhiko;Akira, Shizuo;Yamamoto, Akitsugu;Komuro, Issei;Otsu, Kinya
通讯作者：
Otsu, Kinya
影响因子：
30.5
作者：
Buerckstuemmer, Tilmann;Baumann, Christoph;Superti-Furga, Giulio
通讯作者：
Superti-Furga, Giulio
影响因子：
11.4
作者：
Hansen, Kathrine;Prabakaran, Thaneas;Paludan, Soren R.
通讯作者：
Paludan, Soren R.
影响因子：
16.6
作者：
Jønsson KL;Laustsen A;Krapp C;Skipper KA;Thavachelvam K;Hotter D;Egedal JH;Kjolby M;Mohammadi P;Prabakaran T;Sørensen LK;Sun C;Jensen SB;Holm CK;Lebbink RJ;Johannsen M;Nyegaard M;Mikkelsen JG;Kirchhoff F;Paludan SR;Jakobsen MR
通讯作者：
Jakobsen MR