A New Clue Into the Cause, Spread of Parkinson's Disease?

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A New Clue Into the Cause, Spread of Parkinson's Disease?

Damaged mitochondrial DNA (mtDNA) initiates and spreads Parkinson's disease (PD) pathology, potentially opening new avenues for early diagnosis, disease monitoring, and drug development.

While defects in mitochondrial functions and in mitochondrial DNA have been implicated in PD in the past, the current study demonstrates "for the first time how damaged mitochondrial DNA can underlie the mechanisms of PD initiation and spread in brain," lead investigator Shohreh Issazadeh-Navikas, PhD, with the University of Copenhagen, Denmark, told Medscape Medical News.

"This has direct implication for clinical diagnosis" ― if damaged mtDNA can be detected in blood, it could serve as an early biomarker for disease, she explained.

The study was published online October 2 in Molecular Psychiatry.

"Infectious-like" Spread of PD Pathology

In earlier work, the researchers identified dysregulated interferon-beta (IFNβ) signaling as a "top candidate pathway" associated with sporadic PD and its progression to PD with dementia (PDD).

In mice PD models that were deficient in IFNβ signaling, the investigators showed that neuronal IFNβ is required to maintain mitochondrial homeostasis and metabolism.

Lack of neuronal IFNβ or disruption of its downstream signaling causes the accumulation of damaged mitochondria with excessive oxidative stress and insufficient adenosine triphosphate production.

In the current study, using postmortem brain tissue samples from patients with sporadic PD, they confirmed that that there were deletions of mtDNA in the medial frontal gyrus, a region implicated in cognitive impairments in PD, suggesting a potential role of damaged mtDNA in disease pathophysiology.

They also identified mtDNA deletions in a "hotspot" in complex I respiratory chain subunits that were associated with dysregulation of oxidative stress and DNA damage response pathways in cohorts with sporadic PD and PDD.

They confirmed the contribution of mtDNA damage to PD pathology in the PD mouse models. They showed that lack of neuronal IFNβ signaling leads to oxidative damage and mutations in mtDNA in neurons, which are subsequently released outside the neurons.

Injecting damaged mtDNA into mouse brain induced PDD-like behavioral symptoms, including neuropsychiatric, motor, and cognitive impairments. It also caused neurodegeneration in brain regions distant from the injection site, suggesting that damaged mtDNA triggers spread of PDD characteristics in an "infectious-like" manner, the researchers report.

Further study revealed that the mechanism through which damaged mtDNA causes pathology in healthy neurons involves dual activation of Toll-like receptor (TLR) 9 and 4 pathways, leading to 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," the investigators write.

Looking ahead, they plan to investigate how mtDNA damage can serve as a predictive marker for different disease stages and progression and to explore potential therapeutic strategies aimed at restoring normal mitochondrial function to rectify the mitochondrial dysfunctions implicated in PD.

Making a Comeback?

Commenting on the research for Medscape Medical News, James Beck, PhD, chief scientific officer at the Parkinson's Foundation, noted that the role of mitochondria in PD is "like a starlet that burst onto the scene in the 80s, faded into obscurity, and through diligence and continued research has moved beyond being a solid character actor and is reemerging as a force to reckon with.

"This paper only adds to the allure that mitochondria may have in contributing to PD by providing evidence of a novel process by which mitochondria may be not only contributing to PD and loss of dopamine neurons but may play a larger role in the subsequent effects that many people with PD experience ― dementia," Beck said.

He noted that the authors identified several proteins as facilitating the neurodegeneration that is wrought by damaged mitochondrial DNA.

"These could be potential targets for future drug development. In addition, this work implicates alterations in immune signaling and drugs in development to target inflammatory responses may also bring ancillary benefit," Beck said.

However, he said that "while very interesting findings, this is really the first effort that demonstrates how damaged mitochondrial DNA may contribute to neurodegeneration in the context of PD and PD dementia. Further work needs to validate these findings as well as to elucidate mechanisms underlying the propagation of the mitochondrial DNA from cell to cell."

Funding for this research was provided by the European Union's Horizon 2020 Research and Innovation Program, the Lundbeck Foundation, and the Danish Council for Independent Research–Medicine. Issazadeh-Navikas and Beck have disclosed no relevant financial relationships.

Mol Psychiatry. Published online October 2, 2023. Full text

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