Mitochondrial complex I deficiency occurs in the substantia nigra of individuals with Parkinson's disease. It is generally believed that this phenomenon is caused by accumulating mitochondrial DNA damage in neurons and that it contributes to the process of neurodegeneration. We hypothesized that if these theories are correct, complex I deficiency should extend beyond the substantia nigra to other affected brain regions in Parkinson's disease and correlate tightly with neuronal mitochondrial DNA damage. To test our hypothesis, we employed a combination of semiquantitative immunohistochemical analyses, Western blot and activity measurements, to assess complex I quantity and function in multiple brain regions from an extensively characterized population-based cohort of idiopathic Parkinson's disease (n = 18) and gender and age matched healthy controls (n = 11). Mitochondrial DNA was assessed in single neurons from the same areas by real-time PCR. Immunohistochemistry showed that neuronal complex I deficiency occurs throughout the Parkinson's disease brain, including areas spared by the neurodegenerative process such as the cerebellum. Activity measurements in brain homogenate confirmed a moderate decrease of complex I function, whereas Western blot was less sensitive, detecting only a mild reduction, which did not reach statistical significance at the group level. With the exception of the substantia nigra, neuronal complex I loss showed no correlation with the load of somatic mitochondrial DNA damage. Interestingly, α-synuclein aggregation was less common in complex I deficient neurons in the substantia nigra. We show that neuronal complex I deficiency is a widespread phenomenon in the Parkinson's disease brain which, contrary to mainstream theory, does not follow the anatomical distribution of neurodegeneration and is not associated with the neuronal load of mitochondrial DNA mutation. Our findings suggest that complex I deficiency in Parkinson's disease can occur independently of mitochondrial DNA damage and may not have a pathogenic role in the neurodegenerative process.

中文翻译：

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神经元复合物I缺乏症遍布帕金森氏病脑部，但与神经变性或线粒体DNA损伤无关。

线粒体复合物I缺乏症发生在帕金森氏病患者的黑质中。通常认为，这种现象是由于神经元中线粒体DNA损伤的积累引起的，并且它促进了神经变性的过程。我们假设，如果这些理论是正确的，复杂的I缺乏症应扩展到黑质以外，再扩展到帕金森氏病的其他受影响的大脑区域，并与神经元线粒体DNA损伤紧密相关。为了检验我们的假设，我们结合使用了半定量免疫组化分析，蛋白质印迹和活性检测，以评估广泛基于人群的特发性帕金森病队列中多个脑区域的复杂I数量和功能。病（n = 18），性别和年龄相符的健康对照组（n = 11）。通过实时PCR，对来自相同区域的单个神经元的线粒体DNA进行了评估。免疫组织化学显示，帕金森氏病的整个大脑中都存在神经元复合物I缺乏症，包括神经退行性过程所幸免的区域，例如小脑。脑匀浆中的活性测量结果证实复合物I功能有中等程度的降低，而Western印迹的敏感性较低，仅检测到轻度的降低，在组水平上未达到统计学意义。除黑质外，神经元复合体I的丢失与体细胞线粒体DNA损伤的负荷无关。有趣的是，α-突触核蛋白聚集在黑质中复杂的I缺陷神经元中并不常见。我们显示神经元复杂I缺乏是帕金森氏病大脑中的一种普遍现象，与主流理论相反，它不遵循神经变性的解剖分布，并且与线粒体DNA突变的神经元负荷无关。我们的发现表明，帕金森氏病中复杂的I缺乏症可以独立于线粒体DNA损伤而发生，并且可能在神经变性过程中没有致病作用。