Arguing for Mitochondrial DNA Damage to Spread Between Neurons in Parkinson's Disease

The most noticeable symptoms of Parkinson's disease occur because of the loss of a small but vital population of dopamine-generating neurons in the brain. The condition is associated with the spread of misfolded, aggregated α-synuclein throughout brain tissue. α-synuclein is one of the few molecules in the body capable of misfolding in ways that encourage other molecules o α-synuclein to also misfold in the same way. It can thus spread from cell to cell, perhaps carried in extracellular vesicles. It is thought that misfolding of α-synuclein often first occurs in the intestines, and only then spreads to the brain through the nervous system.

Dopaminergenic neurons are in some way more vulnerable than other cells to the pathological biochemistry that accompanies the presence of misfolded α-synuclein. This vulnerability also appears strongly connected to the function of mitochondria, the power plants of the cell, hundreds found in every neuron. Genetic variants that increase the risk of suffering Parkinson's disease are connected to loss of mitochondrial function and loss of mitochondrial quality control, suggesting that mitochondrial dysfunction is important to the death of neurons in this condition.

One of the mechanisms thought to cause age-related declines in mitochondrial function is mitochondrial DNA damage. Mitochondria are the descendants of ancient symbiotic bacteria, and they still carry their own circular genome. In today's open access paper, the authors provide evidence to suggest that mitochondrial DNA damage can spread from cell to cell in the Parkinson's brain. In addition to an investigation of the biochemistry involved in this transmission of damage, the researchers demonstrate that introducing damaged mitochondrial DNA into the brains of mice produces symptoms that mimic those of Parkinson's disease.

One does have to be careful when looking at studies in which researchers damage the biochemistry of mice in some way and thereafter draw conclusions about aspects of aging and disease. Age-related diseases emerge from damage and dysfunction, so many different forms of damage and dysfunction can mimic specific aspects of aging to some degree, even if they are not all that important in normal aging, even if they are not operating in any meaningful way in normal aging. Whether or not any given study is usefully taking this approach of applying a specific form of damage to mice depends on the details. Here it seems that one can argue that the approach is more rather than less compelling, but it still leaves open the question of the degree to which the mechanism of transmission of damaged mitochondrial DNA is important in the condition.

Mitochondrial DNA damage triggers spread of Parkinson's disease-like pathology

In the field of neurodegenerative diseases, especially sporadic Parkinson's disease (sPD) with dementia (sPDD), the question of how the disease starts and spreads in the brain remains central. While the prion-like proteins resulting from misfolding of α-synuclein have been designated as a culprit, recent studies suggest the involvement of additional factors. We found that oxidative stress, damaged DNA binding, cytosolic DNA sensing, and Toll-Like Receptor (TLR)4/9 activation pathways are strongly associated with the sPDD transcriptome, which has dysregulated type I Interferon (IFN) signaling. In sPD patients, we confirmed deletions of mitochondrial DNA (mtDNA) in the medial frontal gyrus, suggesting a potential role of damaged mtDNA in the disease pathophysiology.

To explore its contribution to pathology, we used spontaneous models of sPDD caused by deletion of type I IFN signaling (Ifnb-/-/Ifnar-/- mice). We found that the lack of neuronal IFNβ/IFNAR leads to oxidization, mutation, and deletion in mtDNA, which is subsequently released outside the neurons. Injecting damaged mtDNA into mouse brain induced PDD-like behavioral symptoms, including neuropsychiatric, motor, and cognitive impairments. Furthermore, it caused neurodegeneration in brain regions distant from the injection site, suggesting that damaged mtDNA triggers spread of PDD characteristics in an "infectious-like" manner.

We also discovered that the mechanism through which damaged mtDNA causes pathology in healthy neurons is independent of Cyclic GMP-AMP synthase and IFNβ/IFNAR, but rather involves the dual activation of TLR9/4 pathways, resulting in increased oxidative stress and neuronal cell death, respectively. Our proteomic analysis of extracellular vesicles containing damaged mtDNA identified the TLR4 activator Ribosomal Protein S3 as a key protein involved in recognizing and extruding damaged mtDNA.

These findings might shed light on new molecular pathways through which damaged mtDNA initiates and spreads PD-like disease, potentially opening new avenues for therapeutic interventions or disease monitoring.