Researchers here suggest that the combined effects of mitochondrial dysfunction and lysosomal dysfunction in long-lived cells in old brains lead to a leakage of mitochondrial DNA into the body of the cell, where it provokes maladaptive inflammatory reactions that continue to the onset and progression of neurodegenerative conditions such as Parkinson's disease. The data is interesting, but needs confirmation in more relevant models than those used to date. The challenge with research into the mechanisms of neurodegeneration is that the animal models are highly artificial. They have relevance to the mechanism under study, but are by no means a reflection of the human condition. At the present time there really is no practical way to show true relevance other than by putting a therapy into people.
A novel finding utilizing cellular and zebrafish models has demonstrated how the leakage of mitochondrial dsDNA into the cytosol environment of the cell can contribute to the impairment of brain tissue of patients with Parkinson's disease (PD). "Our results showed for the first time that cytosolic dsDNA of mitochondrial origin leaking and escaping from lysosomal degradation can induce cytotoxicity both in cultured cells, as well as in zebrafish models of Parkinson's disease. This study showed that the leakage of this mitochondrial nucleic material may occur as a result of mitochondrial dysfunction, which may involve genetic mutations in genes encoding mitochondrial proteins or incomplete degradation of mitochondrial dsDNA in the lysosome - which is a 'degradation factory' of the cell. Upon the leakage into the cytoplasm, this undegraded dsDNA is detected by a 'foreign' DNA sensor of the cytoplasm (IFI16) which then triggers the upregulation of mRNAs encoding for inflammatory proteins."
Using a PD zebrafish model (gba mutant), the researchers demonstrated that a combination of PD-like phenotypes including accumulation of cytosol dsDNA deposits, reduced number of dopaminergic neurons after 3 months. Lastly, they further generated a DNase II mutant zebrafish model which exhibited decreased numbers of dopaminergic neurons and demonstrated accumulated cytosolic DNA. Interestingly, when the gba mutant zebrafish was complemented with human DNAse II gene, the overexpression of human DNAse II decreased cytosolic dsDNA deposits, rescued neuro-degradation by rescuing the number of dopaminergic and noradrenergic neurons after 3 months. This demonstrated that neurodegenerative phenotype of gba mutant zebrafish induced by dsDNA deposits in the cytosol can be restored by DNAse II.
In a step further, to determine the effect of cytosolic dsDNA of mitochondrial origin in human brain with PD, researchers inspected postmortem human brain tissues from patients who were diagnosed with idiopathic PD. They observed abundance of cytosolic dsDNA of mitochondrial origin in medulla oblongata of postmortem brain tissues, the levels of IFI16 were also markedly increased in these brain tissues.