Circulating cell-free mitochondrial DNA levels in Parkinson’s disease are influenced by treatment

Abstract

Several studies have linked circulating cell-free mitochondrial DNA (ccf-mtDNA) to human disease. In particular, reduced ccf-mtDNA levels in the cerebrospinal fluid (CSF) of both Alzheimer's and Parkinson's disease (PD) patients have raised the hypothesis that ccf-mtDNA could be used as a biomarker for neurodegenerative disease onset and progression. However, how a reduction of CSF ccf-mtDNA levels relates to neurodegeneration remains unclear. Many factors are likely to influence ccf-mtDNA levels, such as concomitant therapeutic treatment and comorbidities. In this study we aimed to investigate these factors, quantifying CSF ccf-mtDNA from the Parkinson's Progression Markers Initiative in 372 PD patients and 159 matched controls at two time points. We found that ccf-mtDNA levels appear significantly reduced in PD cases when compared to matched controls and are associated with cognitive impairment. However, our data indicate that this reduction in ccf-mtDNA is also associated with the commencement, type and duration of treatment. Additionally, we found that ccf-mtDNA levels are associated with comorbidities such as depression and insomnia, however this was only significant if measured in the absence of treatment. We conclude that in PD, similar to reports in HIV and sepsis, comorbidities and treatment can both influence ccf-mtDNA homeostasis, raising the possibility that ccf-mtDNA may be useful as a biomarker for treatment response or the development of secondary phenotypes. Given that, clinically, PD manifests often decades after neurodegeneration begins, predicting who will develop disease is important. Also, identifying patients who will respond to existing treatments or develop secondary phenotypes will have increased clinical importance as PD incidence rises.

Post-mortem ventricular cerebrospinal fluid cell-free-mtDNA in neurodegenerative disease

“…In PD, the reduced vCSF-cfmtDNA we observed suggests that reduced cfmtDNA persists throughout the disease course with post-mortem vCSF-cfmtDNA levels comparable to those we observed in early-stage PD lumbar CSF 25,37 . How this relates to the neurodegenerative process in PD remains still unclear as we found no correlation between vCSF-cfmtDNA and neurodegenerative protein markers.…”

“…Since then, cfDNA levels have been linked to a diverse range of phenotypes including sepsis 8 , myocardial infarction 9 and autoimmune disease 10 . More recently, research has demonstrated an association between cell-free-mitochondrial DNA (cfmtDNA) and several complex traits 11 – 23 , particularly neurological and neurodegenerative diseases such as PD 24 , 25 , AD 26 , 27 and multiple sclerosis (MS) 14 , 28 . Its stability in extracellular fluids such as plasma, serum and cerebrospinal fluid has led many studies to suggest that cfmtDNA has utility as a biomarker of disease onset and progression.…”

Circulating Cell-Free Nucleic Acids: Main Characteristics and Clinical Application

“…Reduced cf-mtDNA levels in the cerebrospinal fluid of neurodegenerative disease patients—including Alzheimer’s and Parkinson’s disease as well as multiple sclerosis—have also been reported. However, although reduced cf-mtDNA might be a hallmark of neurodegeneration, the utility of cf-mtDNA as a biomarker of such diseases is limited [ 52 , 53 ].…”

The Role of DNA in the Extracellular Environment: A Focus on NETs, RETs and Biofilms

“…In animals, self-DNA of nuclear or mitochondrial origin is frequently reported to act as a DAMP and to determine various types of diseases. For instance, extracellular self-DNA is associated to several diseases and/or to their severity, like in cancers (Hawes et al, 2015), hypertension (McCarthy et al, 2015, and Parkinson and Alzheimer diseases (Lowes et al, 2020). Self-DNA is also considered to be involved in autoimmune diseases such as in rheumatoid arthritis (Rykova et al, 2017), in systemic lupus erythematosus (Barrat et al, 2005), and in other autoimmune diseases (Vakrakou et al, 2018).…”