Abstract
Understanding the molecular mechanisms underlying the pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, is a major challenge. We used co-expression networks implemented by the SWitch Miner software to identify switch genes associated with drastic transcriptomic changes in the blood of ALS patients. Functional analyses revealed that switch genes were enriched in pathways related to the cell cycle, hepatitis C, and small cell lung cancer. Analysis of switch genes by sex revealed that switch genes from males were associated with metabolic pathways, including PI3K-AKT, sphingolipid, carbon metabolism, FOXO, and AMPK signaling. In contrast, female switch genes related to infectious diseases, inflammation, apoptosis, and atherosclerosis. Furthermore, eight switch genes showed sex-specific gene expression patterns. Collectively, we identified essential genes and pathways that may explain sex differences observed in ALS. Future studies investigating the potential role of these genes in driving disease disparities between males and females with ALS are warranted.
Highlights
Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease, is a devastating neuromuscular disease characterized by the progressive degeneration of motor neurons in the brain and spinal cord
We focused our analysis on blood studies containing human samples from sporadic ALS patients
Understanding sex-specific differences are crucial for patient treatment
Summary
Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease, is a devastating neuromuscular disease characterized by the progressive degeneration of motor neurons in the brain and spinal cord. There is no cure for the disease, and patients frequently die from respiratory paralysis within two to five years after disease onset [1]. Genetic causes account for less than 10% of the cases. Most of the hereditary cases display an autosomal dominant pattern in genes encoding Cu/Zn superoxide dismutase (SOD1), TAR-DNA binding protein 43 (TDP-43, C9ORF72, and fused in sarcoma (FUS)) [2]. Other rare mutations in optineurin (OPN), valosin-containing protein (VCP), and ubiquilin 2 (UBQLN2) have been reported in familial cases [2]. The vast majority of the cases are considered sporadic, suggesting that a complex interaction between genetics and environmental insults is responsible for the disease pathogenesis
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