Genetic contributions to mitochondrial dysfunction in amyotrophic lateral sclerosis etiology
Year: 2026
Type: article
Study design: Observational Study
Abstract: 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 whole-exome sequencing data from 1,034 individuals with ALS were analyzed using two distinct computational tools, which ranked candidate genes based on functional relevance to ALS. POLG, the sole mitochondrial DNA (mtDNA) polymerase, emerged as a top candidate gene. RNA sequencing (RNA-seq) analysis revealed that among genes upregulated in samples with a POLG variant, there was an enrichment for mitochondrial pathways, including 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 control subjects. POLG variant carriers also exhibited an increased burden of mitochondrial genome variants, a pattern shared by carriers of variants in other genes involved in mtDNA maintenance. Additionally, POLG variant carriers had elevated mtDNA 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 mtDNA maintenance defects, altered expression of mitochondrial-related pathways, and impaired mitophagy to the ALS etiology.
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,300
OpenAlex ID: W7153530261