Biosciences Institute, 4th Floor Cookson Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Sci Rep. 2020 Sep 17;10(1):15253. doi: 10.1038/s41598-020-72190-5.
Cell-free mitochondrial DNA (cfmtDNA) is detectable in almost all human body fluids and has been associated with the onset and progression of several complex traits. In-life assessments indicate that reduced cfmtDNA is a feature of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and multiple sclerosis. However, whether this feature is conserved across all neurodegenerative diseases and how it relates to the neurodegenerative processes remains unclear. In this study, we assessed the levels of ventricular cerebrospinal fluid-cfmtDNA (vCSF-cfmtDNA) in a diverse group of neurodegenerative diseases (NDDs) to determine if the in-life observations of reduced cfmtDNA seen in lumbar CSF translated to the post-mortem ventricular CSF. To investigate further, we compared vCSF-cfmtDNA levels to known protein markers of neurodegeneration, synaptic vesicles and mitochondrial integrity. Our data indicate that reduced vCSF-cfmtDNA is a feature specific to Parkinson's and appears consistent throughout the disease course. Interestingly, we observed increased vCSF-cfmtDNA in the more neuropathologically severe NDD cases, but no association to protein markers of neurodegeneration, suggesting that vCSF-cfmtDNA release is more complex than mere cellular debris produced following neuronal death. We conclude that vCSF-cfmtDNA is reduced in PD, but not other NDDs, and appears to correlate to pathology. Although its utility as a prognostic biomarker is limited, our data indicate that higher levels of vCSF-cfmtDNA is associated with more severe clinical presentations; suggesting that it is associated with the neurodegenerative process. However, as vCSF-cfmtDNA does not appear to correlate to established indicators of neurodegeneration or indeed indicators of mitochondrial mass, further work to elucidate its exact role is needed.
无细胞线粒体 DNA（cfmtDNA）几乎存在于所有人体体液中，与多种复杂特征的发生和进展有关。在活体评估中表明，cfmtDNA 减少是帕金森病、阿尔茨海默病和多发性硬化症等神经退行性疾病的特征。然而，这种特征是否在所有神经退行性疾病中都具有保守性，以及它与神经退行性过程的关系如何，尚不清楚。在这项研究中，我们评估了多种神经退行性疾病（NDD）的脑室脑脊液-cfmtDNA（vCSF-cfmtDNA）水平，以确定在腰椎 CSF 中观察到的 cfmtDNA 减少是否与死后脑室 CSF 相关。为了进一步研究，我们将 vCSF-cfmtDNA 水平与已知的神经退行性病变蛋白标志物，即突触小泡和线粒体完整性进行了比较。我们的数据表明，vCSF-cfmtDNA 减少是帕金森病的特征，并且在整个疾病过程中似乎都是一致的。有趣的是，我们观察到更具神经病理学严重程度的 NDD 病例中 vCSF-cfmtDNA 增加，但与神经退行性病变的蛋白标志物没有关联，这表明 vCSF-cfmtDNA 的释放比神经元死亡后产生的单纯细胞碎片更为复杂。我们得出结论，vCSF-cfmtDNA 在 PD 中减少，但在其他 NDD 中没有，并且似乎与病理学相关。尽管它作为预后生物标志物的效用有限，但我们的数据表明，较高水平的 vCSF-cfmtDNA 与更严重的临床表现相关；表明它与神经退行性过程相关。然而，由于 vCSF-cfmtDNA 似乎与既定的神经退行性病变指标或实际上与线粒体质量的指标没有关联，因此需要进一步阐明其确切作用的工作。
