Neurological
New study provides clues as to the cause and possible treatment of Parkinson’s disease
Niigata, Japan – Researchers at the Brain Research Institute at Niigata University, Japan, may have developed a new approach that could revolutionize the treatment, prevention, and potentially reversal of the damage that could lead to Parkinson’s disease (PD). This novel finding, using cell and zebrafish models, demonstrated how the leakage of mitochondrial dsDNA into the cytosolic environment of the cell can contribute to the impairment of brain tissue in patients with Parkinson’s disease.
Parkinson’s disease is the second most common neurodegenerative disease and its prevalence is expected to double over the next 30 years.
These sobering statistics, and the quest to discover prognostic markers for Parkinson’s disease, inspired a team of scientists led by Prof. Hideaki Matsui to build on previous evidence linking mitochondrial dysfunction and lysosomal dysfunction to Parkinson’s disease.
Our results demonstrated for the first time that cytosolic dsDNA of mitochondrial origin that leaks and escapes from lysosomal degradation can induce cytotoxicity in both cultured cells and zebrafish models of Parkinson’s disease. This study showed that leakage of this mitochondrial nucleus can occur as a result of mitochondrial dysfunction, which can include genetic mutations in genes that encode mitochondrial proteins or incomplete breakdown of mitochondrial dsDNA in the lysosome – a “breakdown factory” of the cell. When it escapes into the cytoplasm, this undegraded dsDNA is detected by a “foreign” DNA sensor of the cytoplasm (IFI16), which then triggers the upregulation of mRNAs that code for inflammatory proteins (type I interferon-stimulated cytokines such as IL1β). Although further research is needed, we believe that the subsequent accumulation of inflammatory protein in the cytoplasm can lead to functional imbalance in cells and ultimately cell death.
Prof. Matsui
This dsDNA leakage effect can, however, be counteracted by DNAse II, a dsDNA-degrading agent.
Prof. Akiyoshi Kakita, who was involved in the study as an associate investigator
The first part of the study was carried out in vitro on cells of nerve cancer origin (SH-SY5Y cells) with defective mitochondria and lysosomal dysfunction by knockdown of the GBA, ATP13A and PINK1 genes. The mutated cells showed leakage of dsDNA and accumulation of inflammatory cytokines and cell death. In an additional comparison experiment with mutated cells (with defective mitochondrial proteins) and wild-type SH-SY5Y cells, they also showed that DNAse II rescued cells by breaking down dsDNA.
In a confirmatory study using a PD zebrafish model (gba mutant), the researchers showed that a combination of PD-like phenotypes, including the accumulation of cytosolic dsDNA debris, reduced the number of dopaminergic neurons after 3 months. Finally, they generated a DNase II mutant zebrafish model that had decreased numbers of dopaminergic neurons and showed accumulated cytosolic DNA. Interestingly, overexpression of human DNAse II decreased cytosolic dsDNA deposits when the gba mutant zebrafish was complemented with human DNAse II gene and saved neurodegradation by saving the number of dopaminergic and noradrenergic neurons after 3 months.
This demonstrated that the neurodegenerative phenotype of gba mutant zebrafish induced by dsDNA deposition in the cytosol can be restored by DNAse II.
To determine the effect of cytosolic dsDNA of mitochondrial origin in the human brain with PD, they investigated post-mortem human brain tissue from patients diagnosed with idiopathic PD. They observed an abundance of cytosolic dsDNA of mitochondrial origin in the medulla oblongata of post-mortem brain tissue; the levels of IFI16 were also significantly increased in these brain tissues. In summary, the results of this study showed that cytosolic dsDNA of mitochondrial origin accumulated in PD brains and that these dsDNA deposits and IFI16 play a major role in human PD pathogenesis.
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The article “Cytosolic dsDNA of mitochondrial origins induces cytotoxicity and neurodegeneration in cellular and zebrafish models of Parkinson’s disease” was published in NATURE COMMUNICATIONS at https://doi.org/10.1038/s41467-021-23452-x.