Mitochondrial DNA damage linked to spread of neurodegeneration

Preclinical research may pave way for innovative treatment strategies, scientists say

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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An illustration of a group of neurons, specialized nerve cells.

Damage to the genetic material in mitochondria, cells’ energy production centers, may trigger the spread of nerve cell death in Parkinson’s disease, according to recent research.

Faulty mitochondrial DNA (mtDNA) was observed in patient tissues and mouse models. In lab studies, the damaged mtDNA was found to be released from cells, potentially enabling its spread to others nearby. Injecting it into healthy mice caused widespread neurodegeneration, as well as motor and cognitive problems.

“These findings might shed light on new molecular pathways through which damaged mtDNA initiates and spreads [Parkinson’s]-like disease, potentially opening new avenues for therapeutic interventions or disease monitoring,” the researchers wrote.

The study, “Mitochondrial DNA damage triggers spread of Parkinson’s disease-like pathology,” was published in Molecular Psychiatry.

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In Parkinson’s, nerve cells responsible for producing a signaling chemical called dopamine are progressively lost in the brain’s substantia nigra, causing the hallmark motor symptoms of the disease. Over time, this damage expands, leading to widespread neurodegeneration and significant cognitive disruptions, or dementia. The exact cause of this cell death and its spread is not known.

It has been suggested that dysfunctional mitochondria might play a role. Nerve cells have high energetic demands and may be particularly vulnerable when these organelles, which are responsible for providing cells with the energy they need to function, are damaged or dysfunctional.

Indeed, accumulating preclinical evidence indicates that changes in or damage to mtDNA could be implicated in the neurodegenerative condition. Unlike other cellular organelles, mitochondria have their own genetic material housed directly within them.

“However, there is a large gap in our understanding of the molecular chain of events underlying mitochondrial dysfunctions, their impact on the nature of mtDNA and how damages to mtDNA can further trigger [Parkinson’s] pathology,” the researchers wrote.

Impaired signaling of type 1 interferon (IFN) molecules, including IFN-beta, is associated with Parkinson’s disease and progression to dementia. Type 1 IFN molecules are a group of signaling proteins that play a crucial role in the immune system’s response to viral infections and other immune challenges.

In a previous mouse study, the scientists found that IFN-beta was critical for maintaining proper mitochondrial function. Without it, mitochondria were damaged and energy production impaired.

Linking mitochondrial DNA damage to neurodegeneration

In the recent study, scientists set out to explore the relationship between IFN loss, mtDNA damage, and the spread of neurodegeneration in Parkinson’s disease.

An examination of publicly available gene activity data from groups of people with sporadic Parkinson’s disease and Parkinson’s dementia, who previously had been reported to have IFN dysregulation, indicated the presence of mitochondrial dysfunction relative to healthy people.

This was observed likewise in brain tissue from another group of Parkinson’s patients, where dysfunction of mitochondrial energy production, called oxidative phosphorylation, and evidence of mtDNA damage was observed. Findings in nerve cells from mouse models of Parkinson’s disease dementia caused by a lack of IFN-beta closely mirrored what was seen in the patient tissues.

“These data strongly indicates that dysregulated [oxidative phosphorylation] and mtDNA deletions in brains of [sporadic Parkinson’s] patients are co-associated with defects in type I IFN,” the researchers wrote.

Additional experiments in the mouse nerve cells indicated that the damaged mtDNA was released from the cell, packaged into carriers called extracellular vesicles (EVs). EVs serve as a form of cell-to-cell communication, carrying cargo from one cell to others.

That could be one possible way that damage in one cell spreads to cause neurodegeneration elsewhere, according to the scientists.

A closer look, using healthy mice

To explore further, they treated healthy mouse nerve cells with the damaged mtDNA from the IFN-lacking mice. This led to nerve cell death and oxidative stress, a type of cellular damage linked to mitochondrial dysfunction.

Likewise, when the damaged mtDNA was injected into live healthy mice, the mice developed symptoms consistent with Parkinson’s dementia, including motor problems, anxiety-like behaviors, and cognitive impairments.

Neurodegeneration throughout the brain — including areas nowhere near where the mtDNA had been injected — was observed, suggesting that mtDNA triggers cellular damage in an “infectious-like” manner, according to the researchers.

In a series of other experiments, the researchers identified that this neurotoxic process relied on certain other proteins, namely Rps3, and toll-like receptors 4 and 9 (TLR 4/9).

Altogether, “our data reveal a distinct role of damaged mtDNA in neurotoxicity and the spread of an infectious [Parkinson’s dementia]-like pathology,” the researchers wrote.

Understanding this process, “holds promises in elucidating the mechanisms underlying the propagation of Parkinson’s pathology throughout the brain and its progression to dementia,” they added.

“These insights may pave the way for innovative treatment strategies and monitoring approaches for Parkinson’s disease.”