| RRC ID |
65116
|
| 著者 |
Matsui H, Ito J, Matsui N, Uechi T, Onodera O, Kakita A.
|
| タイトル |
Cytosolic dsDNA of mitochondrial origin induces cytotoxicity and neurodegeneration in cellular and zebrafish models of Parkinson's disease.
|
| ジャーナル |
Nat Commun
|
| Abstract |
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.
|
| 巻・号 |
12(1)
|
| ページ |
3101
|
| 公開日 |
2021-5-25
|
| DOI |
10.1038/s41467-021-23452-x
|
| PII |
10.1038/s41467-021-23452-x
|
| PMID |
34035300
|
| PMC |
PMC8149644
|
| MeSH |
Animals
Animals, Genetically Modified
Brain / metabolism
Brain / pathology
Brain / ultrastructure
Cell Line, Tumor
Cell Survival / genetics
Cytosol / metabolism
DNA / genetics*
DNA / metabolism
Disease Models, Animal*
Endodeoxyribonucleases / genetics
Endodeoxyribonucleases / metabolism
HEK293 Cells
HeLa Cells
Humans
Microscopy, Electron
Mitochondria / genetics*
Mitochondria / metabolism
Parkinson Disease / genetics*
Parkinson Disease / metabolism
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Zebrafish / genetics*
Zebrafish / metabolism
|
| IF |
12.121
|
| リソース情報 |
| ヒト・動物細胞 |
293T(RCB2202) |
