Biochemistry and Molecular Genetics Department, Hospital Clinic of Barcelona, C/Villarroel, 170, 08036, Barcelona, Spain.
CIBER of Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
Mol Neurobiol. 2022 Feb;59(2):1230-1237. doi: 10.1007/s12035-021-02673-7. Epub 2022 Jan 3.
Hexanucleotide repeat expansion in C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Loss of C9ORF72 protein function and a toxic gain-of-function directly by the RNA or RAN translation have been proposed as triggering pathological mechanisms, along with the accumulation of TDP-43 protein. In addition, mitochondrial defects have been described to be a major driver of disease initiation. Mitochondrial DNA copy number has been proposed as a useful biomarker of mitochondrial dysfunction. The aim of our study was to determine the presence of mtDNA copy number alterations in C9ALS/FTD patients. Therefore, we assessed mtDNA copy number in postmortem prefrontal cortex from 18 C9ORF72 brain donors and 9 controls using digital droplet PCR. A statistically significant decrease of 50% was obtained when comparing C9ORF72 samples and controls. This decrease was independent of age and sex. The reduction of mtDNA copy number was found to be higher in patients' samples presenting abundant TDP-43 protein inclusions. A growing number of studies demonstrated the influence of mtDNA copy number reduction on neurodegeneration. Our results provide new insights into the role of mitochondrial dysfunction in the pathogenesis of C9ALS/FTD.
C9ORF72 基因中的六核苷酸重复扩展是肌萎缩侧索硬化症和额颞叶痴呆（C9ALS/FTD）最常见的遗传原因。已经提出了 C9ORF72 蛋白功能丧失和 RNA 或 RAN 翻译的直接毒性获得性功能障碍作为触发病理机制的原因，同时还伴随着 TDP-43 蛋白的积累。此外，线粒体缺陷被描述为疾病起始的主要驱动因素。线粒体 DNA 拷贝数已被提议作为线粒体功能障碍的有用生物标志物。我们研究的目的是确定 C9ALS/FTD 患者是否存在 mtDNA 拷贝数改变。因此，我们使用数字液滴 PCR 评估了 18 名 C9ORF72 脑供体和 9 名对照者死后前额叶皮层中的 mtDNA 拷贝数。与对照组相比，C9ORF72 样本的 mtDNA 拷贝数统计学上显著降低了 50%。这种减少与年龄和性别无关。在患者样本中发现 TDP-43 蛋白包涵体丰富的情况下，mtDNA 拷贝数的减少更为明显。越来越多的研究表明 mtDNA 拷贝数减少对神经退行性变的影响。我们的结果为线粒体功能障碍在 C9ALS/FTD 发病机制中的作用提供了新的见解。
