Section of Cellular and Molecular Neurobiology, IRCCS Mondino Foundation, Pavia, Italy.
Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
Mov Disord. 2024 Feb;39(2):294-304. doi: 10.1002/mds.29643. Epub 2023 Nov 25.
Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is associated with prodromal Parkinson's disease (PD), but the mechanisms linking phenoconversion of iRBD to PD have not yet been clarified. Considering the association between mitochondrial dysfunction and sleep disturbances in PD, we explored mitochondrial activity in fibroblasts derived from iRBD patients to identify a biochemical profile that could mark the presence of impending neurodegeneration.
The study involved 28 participants, divided into three groups: patients diagnosed with iRBD, PD patients converted from iRBD (RBD-PD), and healthy controls. We performed a comprehensive assessment of mitochondrial function, including an examination of mitochondrial morphology, analysis of mitochondrial protein expression levels by western blot, and measurement of mitochondrial respiration using the Seahorse XFe24 analyzer.
In basal conditions, mitochondrial respiration did not differ between iRBD and control fibroblasts, but when cells were challenged with a higher energy demand, iRBD fibroblasts exhibited a significant (P = 0.006) drop in maximal and spare respiration compared to controls. Interestingly, RBD-PD patients showed the same alterations with a further significant reduction in oxygen consumption linked to adenosine triphosphate production (P = 0.032). Moreover, RBD-PD patients exhibited a significant decrease in protein levels of complexes III (P = 0.02) and V (P = 0.002) compared to controls, along with fragmentation of the mitochondrial network. iRBD patients showed similar, but milder alterations.
Altogether, these findings suggest that mitochondrial dysfunctions in individuals with iRBD might predispose to worsening of the bioenergetic profile observed in RBD-PD patients, highlighting these alterations as potential predictors of phenoconversion to PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
特发性快速眼动（REM）睡眠行为障碍（iRBD）与前驱帕金森病（PD）相关，但将 iRBD 向 PD 的表型转化的机制尚不清楚。鉴于线粒体功能障碍与 PD 中的睡眠障碍之间的关联，我们探索了源自 iRBD 患者的成纤维细胞中的线粒体活性，以确定一种可能标志着即将发生神经退行性变的生化特征。
该研究纳入了 28 名参与者，分为三组：iRBD 患者、由 iRBD 转化而来的 PD 患者（RBD-PD）和健康对照者。我们对线粒体功能进行了全面评估，包括检查线粒体形态、通过 Western blot 分析线粒体蛋白表达水平，以及使用 Seahorse XFe24 分析仪测量线粒体呼吸。
在基础条件下，iRBD 和对照组成纤维细胞的线粒体呼吸没有差异，但当细胞受到更高能量需求的挑战时，iRBD 成纤维细胞的最大和备用呼吸明显下降（P = 0.006），与对照相比。有趣的是，RBD-PD 患者表现出相同的改变，并且与三磷酸腺苷（ATP）生成相关的耗氧量进一步显著降低（P = 0.032）。此外，与对照组相比，RBD-PD 患者的复合物 III（P = 0.02）和 V（P = 0.002）蛋白水平显著降低，同时线粒体网络碎片化。iRBD 患者表现出类似但更轻微的改变。
总之，这些发现表明，iRBD 个体的线粒体功能障碍可能导致 RBD-PD 患者观察到的生物能量谱恶化，突出了这些改变作为向 PD 表型转化的潜在预测因子。© 2023 作者。运动障碍由 Wiley 期刊代表国际帕金森和运动障碍协会出版。
