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Cytosolic dsDNA of mitochondrial origin induces cytotoxicity and neurodegeneration in cellular and zebrafish models of Parkinson's disease.

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.

SUBMITTER: Matsui H

PROVIDER: S-EPMC8149644 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Microglial polarization and the subsequent neuroinflammatory response were identified as key contributors to the progress of Parkinson's disease (PD). Researchers have shown that fibroblast growth factor 21 (FGF21) plays multiple biological functions, including anti-inflammation and neuroprotection. However, the knowledge of FGF21 on microglial polarization in PD in vivo is far from completion. In this study, both in vivo and in vitro models were used to investigate whether FGF21 enhances the brain function by modulating microglial polarization in PD. The protective effects of FGF21 in vivo were conducted using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mice model alongside intraperitoneally received FGF21. A behavioral test battery and tyrosine hydroxylase (TH) immunohistochemistry were conducted to evaluate the neuronal function and nigrostriatal tract integrity. Immunofluorescence assay and Western blot were used to examine M1/M2 microglial polarization. Then, a microglia-neuron co-culture system was adopted in vitro to identify the underlying molecular mechanisms of FGF21. The results showed that FGF21 significantly alleviated motor and cognitive impairment in mice with PD. FGF21 also protected TH-positive neuron cells in the striatum and midbrain. Mechanistically, FGF21 suppressed M1 microglial polarization and the subsequent mRNA expression of pro-inflammatory factors while promoting M2 microglial polarization with increasing anti-inflammatory factors in mice with PD. Furthermore, sirtuin 1 (SIRT1) and the nuclear factor-kappa B (NF-κB) pathway were involved in the FGF21-induced M2 microglial polarization. Conversely, SIRT1 inhibitor EX527 significantly prevented both the FGF21-induced SIRT1 expression and M2 microglial polarization. Moreover, FGF21 pretreatment of microglia significantly prevented neuronal cell apoptosis in a microglia-neuron co-culture system. In conclusion, our data demonstrate that FGF21 exerted its protective effects in the pathology of PD through SIRT1/NF-κB pathway-mediated microglial polarization. Given the safety record of human clinical trials, FGF21 could be a promising therapy for clinical trials to ameliorate motor and nonmotor deficits in patients with PD.

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Cytosolic dsDNA of mitochondrial origin induces cytotoxicity and neurodegeneration in cellular and zebrafish models of Parkinson's disease.

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