Properties of Extracellular DNA from the Cerebrospinal Fluid and Blood Plasma during Parkinson’s Disease

Glebova, K. V.; Конорова, И. Л.; Полещук, В.В.; Байдакова, Г. В.; Вейко, Н. Н.

doi:10.1007/s10517-014-2461-9

Cited by 6 publications

(3 citation statements)

References 13 publications

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“…The promoting effect of DNA on tau aggregation was observed www.nature.com/scientificreports www.nature.com/scientificreports/ in a wide range of concentrations from 10 to 1000 ng. The use of these concentrations were informed by the range of cerebrospinal fluid DNA concentrations observed in patients with different diseases: 1-600 ng/mL [48][49][50] . The sources of bacterial and fungal DNA were selected based on the literature and personal data that showed associations of certain microorganisms with AD.…”

Section: Discussionmentioning

confidence: 99%

Bacterial DNA promotes Tau aggregation

Tetz

Pinho²,

Pritzkow³

et al. 2020

Sci Rep

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A hallmark feature of Alzheimer's disease (AD) and other tauopathies is the misfolding, aggregation and cerebral accumulation of tau deposits. Compelling evidence indicates that misfolded tau aggregates are neurotoxic, producing synaptic loss and neuronal damage. Misfolded tau aggregates are able to spread the pathology from cell-to-cell by a prion like seeding mechanism. The factors implicated in the initiation and progression of tau misfolding and aggregation are largely unclear. In this study, we evaluated the effect of DNA extracted from diverse prokaryotic and eukaryotic cells in tau misfolding and aggregation. Our results show that DNA from various, unrelated gram-positive and gram-negative bacteria results in a more pronounced tau misfolding compared to eukaryotic DNA. Interestingly, a higher effect in promoting tau aggregation was observed for DNA extracted from certain bacterial species previously detected in the brain, CSF or oral cavity of patients with AD. Our findings indicate that microbial DNA may play a previously overlooked role in the propagation of tau protein misfolding and AD pathogenesis, providing a new conceptual framework that positions the compromised blood-brain and intestinal barriers as important sources of microbial DNA in the CNS, opening novel opportunities for therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Bacterial DNA promotes Tau aggregation

Tetz

Pinho²,

Pritzkow³

et al. 2020

Sci Rep

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“…The response to the DNA fragments in the medium can also vary in the brain cells. At the same time, our recent studies have shown that the response of neurons to changes in cfDNA properties has much in common with the response of other tissues’ cells to cfDNA fragments [ 23 , 69 , 70 ]. In the brain, with an intact blood–brain barrier, cfDNA fragments circulate in the extracellular medium, the composition of which may differ significantly from the plasma cfDNA.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Analysis of Biological Activity of Circulating Cell-Free DNA Isolated from Blood Plasma of Schizophrenic Patients and Healthy Controls

Ershova

Shmarina

Porokhovnik

et al. 2022

Genes

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Schizophrenia is associated with low-grade systemic inflammation. Circulating cell-free DNA (c-cfDNA) belongs to the DAMP class. The major research question was: can the c-cfDNA of schizophrenic patients (sz-cfDNA) stimulate the DNA sensor genes, which control the innate immunity? We investigated the in vitro response of ten human skin fibroblast (HSF) lines to five DNA probes containing different amounts of a GC-rich marker (the ribosomal repeat) and a DNA oxidation marker (8-oxodG) including sz-cfDNA and healthy control c-cfDNA (hc-cfDNA) probes. After 1 h, 3 h, and 24 h of incubation, the expression of 6 protein genes responsible for cfDNA transport into the cell (EEA1 and HMGB1) and the recognition of cytosolic DNA (TLR9, AIM2, STING and RIG-I) was analyzed at the transcriptional (RT-qPCR) and protein level (flow cytometry and fluorescence microscopy). Additionally, we analyzed changes in the RNA amount of 32 genes (RT-qPCR), which had been previously associated with different cellular responses to cell-free DNA with different characteristics. Adding sz-cfDNA and hc-cfDNA to the HSF medium in equal amounts (50 ng/mL) blocked endocytosis and stimulated TLR9 and STING gene expression while blocking RIG-I and AIM2 expression. Sz-cfDNA and hc-cfDNA, compared to gDNA, demonstrated much stronger stimulated transcription of genes that control cell proliferation, cytokine synthesis, apoptosis, autophagy, and mitochondrial biogenesis. No significant difference was observed in the response of the cells to sz-cfDNA and hc-cfDNA. Sz-cfDNA and hc-cfDNA showed similarly high biological activity towards HSFs, stimulating the gene activity of TLR9 and STING DNA sensor proteins and blocking the activity of the AIM2 protein gene. Since the sz-cfDNA content in the patients’ blood is several times higher than the hc-cfDNA content, sz-cfDNA may upregulate pro-inflammatory cytokines in schizophrenia.

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“…There are no data on the concentration of bacterial DNA in the brain tissue of CSF of patients with AD. Thus, the concentration of bacterial DNA used was approximated based on the range of CSF DNA concentrations, from 1 ng/mL to 600 ng/mL, observed in patients with different diseases [60][61][62].…”

Section: Discussionmentioning

confidence: 99%

Bacterial Extracellular DNA Promotes β-Amyloid Aggregation

Tetz

2021

Microorganisms

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Alzheimer’s disease is associated with prion-like aggregation of the amyloid β (Aβ) peptide and the subsequent accumulation of misfolded neurotoxic aggregates in the brain. Therefore, it is critical to clearly identify the factors that trigger the cascade of Aβ misfolding and aggregation. Numerous studies have pointed out the association between microorganisms and their virulence factors and Alzheimer’s disease; however, their exact mechanisms of action remain unclear. Recently, we discovered a new pathogenic role of bacterial extracellular DNA, triggering the formation of misfolded Tau aggregates. In this study, we investigated the possible role of DNA extracted from different bacterial and eukaryotic cells in triggering Aβ aggregation in vitro. Interestingly, we found that the extracellular DNA of some, but not all, bacteria is an effective trigger of Aβ aggregation. Furthermore, the acceleration of Aβ nucleation and elongation can vary based on the concentration of the bacterial DNA and the bacterial strain from which this DNA had originated. Our findings suggest that bacterial extracellular DNA might play a previously overlooked role in the Aβ protein misfolding associated with Alzheimer’s disease pathogenesis. Moreover, it highlights a new mechanism of how distantly localized bacteria can remotely contribute to protein misfolding and diseases associated with this process. These findings might lead to the use of bacterial DNA as a novel therapeutic target for the prevention and treatment of Alzheimer’s disease.

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Properties of Extracellular DNA from the Cerebrospinal Fluid and Blood Plasma during Parkinson’s Disease

Cited by 6 publications

References 13 publications

Bacterial DNA promotes Tau aggregation

Bacterial DNA promotes Tau aggregation

In Vitro Analysis of Biological Activity of Circulating Cell-Free DNA Isolated from Blood Plasma of Schizophrenic Patients and Healthy Controls

Bacterial Extracellular DNA Promotes β-Amyloid Aggregation

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