Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with multiple genetic causes. Given the strong evidence of mitochondrial dysfunction in ALS, this study aimed to identify genetic contributors to ALS by focusing on genes involved in mitochondrial function. Whole-genome and exome sequencing data from 1,034 ALS cases were analyzed using two distinct computational tools, which ranked candidate genes based on functional relevance to ALS. POLG, the sole mitochondrial DNA polymerase, emerged as a top candidate gene. RNA-seq analysis revealed that among genes upregulated in samples with a POLG variant, there was an enrichment for mitochondrial pathways such as translation, localization, and mitophagy. It also revealed variants in POLG and SOD1, a well-known ALS gene, to be the most enriched in samples with expression profiles of mitochondrial-related genes that differed most from those of unaffected controls. POLG variant carriers also exhibited an increased burden of mitochondrial genome variants, a pattern shared by carriers of variants in other genes involved in mitochondrial DNA maintenance. Additionally, POLG variant carriers had elevated mitochondrial DNA copy number (mtDNA-CN), similar to carriers of variants in mitophagy-related genes, suggesting impaired mitophagy. Together, these findings implicate POLG as an ALS-associated gene and link mitochondrial DNA maintenance defects, altered expression of mitochondrial-related pathways, and impaired mitophagy to ALS etiology.
Russell et al. (Wed,) studied this question.