medicalxpress.com/news/2023...
Study:
nature.com/articles/s41380-...
Abstract:
"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 prion-like proteins 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 (mt)DNA 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."
Discussion:
"...Significantly, we demonstrated that damaged mtDNA, resulting from impaired neuronal IFNβ-IFNAR signaling, does not only induce PDD-like pathology upon injection into healthy animals, including causing motor and cognitive deficits, pα-synuclein accumulation, and neuronal loss, it also triggers the spread of the pathology to other brain regions in an “infectious-like manner”. The precise mechanisms of this spread are still to be elucidated, but the impact of damaged mtDNA on TLR9-mediated mitochondrial membrane potential reduction and oxidative stress increase suggests that damaged mtDNA could spread mitochondrial dysfunction to neighbouring healthy neurons. This is supported by the observed increase in neuronal oxDJ1, not only at the injection site but also in distant brain regions. Interestingly, previous studies have demonstrated that oxidative stress promotes prion-like protein aggregation..."
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