Circulating cell-free mitochondrial DNA levels in Parkinson’s disease are influenced by treatment (original) (raw)
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A mitochondrial blood-based patient stratification candidate biomarker for Parkinson’s disease
2022
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and neuroprotective interventions remain elusive. High throughput biomarkers aimed to stratify patients based on shared etiology is one critical path to the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region-specific mitochondrial DNA (mtDNA) damage accumulation in neuronal and in vivo PD models, as well as human PD postmortem brain tissue. In this study, to investigate mtDNA damage as a potential blood biomarker for PD, we describe a novel Mito DNADX assay that allows for the accurate real-time quantification of mtDNA damage in a 96-well platform, compatible with assessing large cohorts of patient samples. We found that levels of mtDNA damage were increased in blood derived from early-stage idiopathic PD patients or those harboring the pathogenic LRRK2 G2019S mutation compared to age-mat...
Journal of Neuropathology & Experimental Neurology, 2002
Inhibition of mitochondrial respiratory chain function may contribute to dopaminergic neurodegeneration in the substantia nigra (SN) of patients with Parkinson disease (PD). Since large-scale structural changes (e.g. deletions and rearrangements in mitochondrial DNA [mtDNA]) have been associated with mitochondrial dysfunction, we tested the hypothesis that increased total mtDNA deletions/rearrangements are associated with neurodegeneration in PD. This study employed a well-established technique, long-extension polymerase chain reaction (LX-PCR), to detect the multiple mtDNA deletions/ rearrangements in the SN of patients with PD, multiple system atrophy (MSA), dementia with Lewy bodies (DLB), Alzheimer disease (AD), and age-matched controls. We also compared the total mtDNA deletions/rearrangements in different brain regions of PD patients. The results demonstrated that both the number and variety of mtDNA deletions/rearrangements were selectively increased in the SN of PD patients compared to patients with other movement disorders as well as patients with AD and age-matched controls. In addition, increased mtDNA deletions/rearrangements were observed in other brain regions in PD patients, indicating that mitochondrial dysfunction is not just limited to the SN of PD patients. These data suggest that accumulation of total mtDNA deletions/rearrangements is a relatively specific characteristic of PD and may be one of the contributing factors leading to mitochondrial dysfunction and neurodegeneration in PD.
Analysis of mitochondrial DNA allelic changes in Parkinson’s disease: a preliminary study
Aging Clinical and Experimental Research, 2019
Background Mitochondrial DNA (mtDNA) mutations are considered as a possible primary cause of age-associated neurodegenerative disorders like Parkinson's disease (PD). Aims To analyze, along the whole mtDNA sequence of PD patients, the presence of non-reference alleles compared to reference alleles, as defined in the revised Cambridge Reference Sequence (rCRS). Methods mtDNA was extracted from whole blood of PD and control groups, and was sequenced using a chip-based resequencing system. Results 58 nucleotide positions (np) exhibited a different allelic distribution in the two groups; in 81% of them the nonreference alleles were over-represented in PD patients, similar to findings reported in patients with Alzheimer's disease, albeit in reduced proportion. Closer analysis of the 58 np in PD group showed that they were characterized by low-level heteroplasmy, and that the nucleotide substitutions determined an amino acid change in 84% of cases. Conclusions These results suggest that mtDNA allelic changes are increased in PD and that age-related neurodegenerative diseases could share a common mechanism involving mtDNA.
Mitochondrial DNA analysis in Parkinson's disease
Movement Disorders, 1990
The reduced form of nicotinamide adenine dinucleotide coenzyme Q reductase (complex I) activity has recently been shown to be deficient in the substantia nigra of patients dying with Parkinson's disease. This biochemical defect is identical to that produced by the neurotoxin 1-methyl-Cphenyl-1,2,3,6-tetrahydropyridine (MPTP), which also produces parkinsonism in humans. Complex I comprises 25 polypeptides, seven of which are encoded by mitochondrial DNA. Restriction fragment analysis of substantia nigra DNA from six patients with Parkinson's disease did not show any major deletion. In two cases, there were different novel polymorphisms that were not observed in control brain (n = 6) or blood (n = 34) samples. RE. Inhibition of NADHlinked oxidation in brain mitochondria by MPP', a metabolite of the neurotoxin MPTP. Life Sci 1985;36:2503-2508. Denton T, Howard BD. A dopaminergic cell line variant resistant to the neurotoxin MPTP. J Neurochern 1987;49: 622-630. Schapira AHV, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD. Mitochondrial Complex I deficiency in Parkinson's disease. Lancet 1989;l: 1269. Schapira AHV, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondria1 Complex I deficiency in Parkinson's disease. J Neurochem 1990;54:823-827. Chomyn A, Mariottini P, Cleeter MJW, Ragan CI, Doolittle RF, Yagi MA, Hatefi Y, Attardi G. Functional assignment of the unidentified reading frames of human mitochondrial DNA. In: Quagliariello E, Slater EC, Palmieri F, Saccone C, Kroon AM, eds. Achievements and perspectives in mitochondrial research, volume ii. Amsterdam: Elsevier Science Publishers, 1987: 259-275. Holt IJ, Harding AE, Morgan-Hughes J. Deletions of mitochondrial DNA in patients with mitochondrial myopathy. Nature 1988;33 1 :717-719. Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J A401 Bioll975; Feinberg AP, Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 1983;132:613. 98503-517.
Mitochondrial haplogroups and cognitive progression in Parkinson’s disease
Brain, 2022
Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4,064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U # had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macrohaplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% CI 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests
Genes
Parkinson’s disease (PD) pathophysiology includes mitochondrial dysfunction, neuroinflammation, and aging as its biggest risk factors. Mitochondrial DNA copy number (mtDNA-CN) and telomere length (TL) are biological aging markers with inconclusive results regarding their association with PD. A case–control study was used to measure TL and mtDNA-CN using qPCR in PBMCs. PD patients were naive at baseline (T0) and followed-up at one (T1) and two (T2) years after the dopaminergic treatment (DRT). Plasmatic cytokines were determined by ELISA in all participants, along with clinical parameters of patients at T0. While TL was shorter in patients vs. controls at all time points evaluated (p < 0.01), mtDNA-CN showed no differences. An increase in mtDNA-CN and TL was observed in treated patients vs. naive ones (p < 0.001). Our statistical model analyzed both aging markers with covariates, showing a strong correlation between them (r = 0.57, p < 0.01), and IL-17A levels positively cor...
2009
1Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sihhiye Ankara, Turkey 2Department of Biochemistry, Faculty of Medicine, Hacettepe University, 06100 Sihhiye Ankara, Turkey 3Department of Basic Medical Sciences, Faculty of Medicine, Near East University, Nicosia, Mersin 10, Turkey 4Department of Neurology, Ankara Research and Training Hospital, 06100 Sihhiye Ankara, Turkey
Mitochondrial alterations in Parkinson’s disease: new clues
Journal of Neurochemistry, 2008
Mitochondrial dysfunction has long been associated with Parkinson's disease (PD). In particular, complex I impairment and subsequent oxidative stress have been widely demonstrated in experimental models of PD and in post-mortem PD samples. A recent wave of new studies is providing novel clues to the potential involvement of mitochondria in PD. In particular, (i) mitochondria-dependent programmed cell death pathways have been shown to be critical to PD-related dopaminergic neurodegeneration, (ii) many disease-causing proteins associated with familial forms of PD have been demonstrated to interact either directly or indirectly with mitochondria, (iii) aging-related mitochondrial changes, such as alterations in mitochondrial DNA, are increasingly being associated with PD, and (iv) anomalies in mitochondrial dynamics and intra-neuronal distribution are emerging as critical participants in the pathogenesis of PD. These new findings are revitalizing the field and reinforcing the potential role of mitochondria in the pathogenesis of PD. Whether a primary or secondary event, or part of a multifactorial pathogenic process, mitochondrial dysfunction remains at the forefront of PD research and holds the promise as a potential molecular target for the development of new therapeutic strategies for this devastating, currently incurable, disease.
A mitochondrial etiology of Alzheimer and Parkinson disease
Biochimica Et Biophysica Acta-general Subjects, 2000
BackgroundThe genetics and pathophysiology of Alzheimer Disease (AD) and Parkinson Disease (PD) appears complex. However, mitochondrial dysfunction is a common observation in these and other neurodegenerative diseases.
Clinical Chemistry, 2021
Background Mitochondrial diseases (MD) are genetic metabolic disorders that impair normal mitochondrial structure or function. The aim of this study was to investigate the status of circulating cell-free mitochondrial DNA (ccfmtDNA) in cerebrospinal fluid (CSF), together with other biomarkers (growth differentiation factor-15 [GDF-15], alanine, and lactate), in a cohort of 25 patients with a molecular diagnosis of MD. Methods Measurement of ccfmtDNA was performed by using droplet digital PCR. Results The mean copy number of ccfmtDNA was approximately 6 times higher in the MD cohort compared to the control group; patients with mitochondrial deletion and depletion syndromes (MDD) had the higher levels. We also detected the presence of both wild-type mtDNA and mtDNA deletions in CSF samples of patients with single deletions. Patients with MDD with single deletions had significantly higher concentrations of GDF-15 in CSF than controls, whereas patients with point mutations in mitochondr...