Network Analysis Identifies Sex-Specific Gene Expression Changes in Blood of Amyotrophic Lateral Sclerosis Patients

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.

Key Disease Mechanisms Linked to Amyotrophic Lateral Sclerosis in Spinal Cord Motor Neurons

“…For instance, CRISPR/Cas9 gene-editing of HERV-K reduced the expression of SF2/ASF (splicing factor 2/alternative splicing factor) and TDP-43 mRNA levels in vitro (Ibba et al, 2018 ). Recently, switch genes identified in the blood of ALS were enriched in pathways related to viral infection (Santiago et al, 2021 ). Interestingly, switch genes identified in the female datasets were associated with the Epstein-Barr virus, hepatitis B, and hepatitis C. The link between viral infection and carcinogenesis and ALS warrants further investigation.…”

“…Another study reported that dysregulated expression of astrocyte elevated gene 1 (AEG1) and the inhibition of the PI3K-AKT pathway were associated with cell death in ALS motor neurons (Yin et al, 2015 ). Moreover, PI3K-AKT was the most significantly enriched pathway identified in switch genes obtained from males with ALS (Santiago et al, 2021 ). These studies suggest that targeting the PI3K-AKT pathway may be a possible therapeutic route in ALS.…”

“…Consistently with these findings, our previous study identified sex-specific switch genes and pathways in the blood of ALS patients. Notably, estradiol was found among the potential drugs for females with ALS (Santiago et al, 2021 ). The possible neuroprotective effects of estradiol warrant further investigation in larger clinical trials.…”

“…Switch genes were enriched in viral carcinogenesis, cell cycle, PI3K-Akt, focal adhesion, proteoglycans in cancer, colorectal cancer, and thyroid hormone signaling. Specifically, pathways related to viral carcinogenesis and hepatitis have been identified in transcriptomic studies from the blood of ALS patients (Santiago et al, 2021 ). The precise linkage between viral infection and the development of ALS has not been thoroughly investigated.…”

“…For example, co-expression network analyses identified key switch genes in the brain of Alzheimer’s disease, frontotemporal dementia, and vascular dementia (Potashkin et al, 2019 , 2020 ). More relevant to the present study, analysis of co-expression networks identified sex-specific switch genes and pathways in the blood of ALS patients (Santiago et al, 2021 ). This study expands our analyses to identify switch genes and pathways in spinal cord motor neurons in ALS patients.…”