PDF(Pubmed)
Abstract：
Amyotrophic Lateral Sclerosis (ALS) is a progressive disease with prevalent mitochondrial dysfunctions affecting both upper and lower motor neurons in the motor cortex, brainstem, and spinal cord. Despite mitochondria having their own genome (mtDNA), in humans, most mitochondrial genes are encoded by the nuclear genome (nDNA). Our study aimed to simultaneously screen for nDNA and mtDNA genomes to assess for specific variant enrichment in ALS compared to control tissues. Here, we analysed whole exome (WES) and whole genome (WGS) sequencing data from spinal cord tissues, respectively, of 6 and 12 human donors. A total of 31,257 and 301,241 variants in nuclear-encoded mitochondrial genes were identified from WES and WGS, respectively, while mtDNA reads accounted for 73 and 332 variants. Despite technical differences, both datasets consistently revealed a specific enrichment of variants in the mitochondrial Control Region (CR) and in several of these genes directly associated with mitochondrial dynamics or with Sirtuin pathway genes within ALS tissues. Overall, our data support the hypothesis of a variant burden in specific genes, highlighting potential actionable targets for therapeutic interventions in ALS.
摘要：
肌萎缩性侧索硬化症（ALS）是一种进行性疾病，普遍存在线粒体功能障碍，影响运动皮质中的上下运动神经元。脑干,和脊髓。尽管线粒体有自己的基因组（mtDNA），在人类中,大多数线粒体基因由核基因组（nDNA）编码。我们的研究旨在同时筛选nDNA和mtDNA基因组，以评估与对照组织相比ALS中的特定变体富集。这里,我们分析了来自脊髓组织的全外显子组（WES）和全基因组（WGS）测序数据，分别,6和12个人类捐赠者。从WES和WGS中鉴定出了核编码线粒体基因中的总共31,257和301,241个变体，分别,而mtDNA读数占73和332个变体。尽管技术上存在差异,这两个数据集一致地揭示了线粒体控制区(CR)和ALS组织内与线粒体动力学或Sirtuin途径基因直接相关的几个基因中变异体的特异性富集。总的来说,我们的数据支持特定基因变异负担的假设，强调ALS治疗干预的潜在可行目标。
