Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. The causative pathogenic mechanisms in ALS remain unclear, limiting the development of treatment strategies. Neuroinflammation and immune dysregulation were involved in the disease onset and progression of several neurodegenerative disorders, including ALS. In this study, we carried out a bioinformatic analysis using publicly available datasets from Gene Expression Omnibus (GEO) to investigate the role of immune cells and genes alterations in ALS. Single-sample gene set enrichment analysis revealed that the infiltration of multiple types of immune cells, including macrophages, type-1/17 T helper cells, and activated CD4 + /CD8 + T cells, was higher in ALS patients than in controls. Weighted gene correlation network analysis identified immune genes associated with ALS. The Gene Ontology analysis revealed that receptor and cytokine activities were the most highly enriched terms. Pathway analysis showed that these genes were enriched not only in immune-related pathways, such as cytokine-cytokine receptor interaction, but also in PI3K-AKT and MAPK signaling pathways. Nineteen immune-related genes (C3AR1, CCR1, CCR5, CD86, CYBB, FCGR2B, FCGR3A, HCK, ITGB2, PTPRC, TLR1, TLR2, TLR7, TLR8, TYROBP, VCAM1, CD14, CTSS, and FCER1G) were identified as hub genes based on least absolute shrinkage and selection operator analysis. This gene signature could differentiate ALS patients from non-neurological controls (p < 0.001) and predict disease occurrence (AUC = 0.829 in training set; AUC = 0.862 in test set). In conclusion, our study provides potential biomarkers of ALS for disease diagnosis and therapeutic monitoring.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder predominantly affecting motor neurons
We focused on 12 types of immune cell that were shown to be associated with ALS in previous studies (Malaspina et al, 2015), including macrophages, regulatory T cells (Tregs), type-1 T helper cells (Th1), type-2 T helper cells (Th2), type-17 T helper cells (Th17), activated CD4 + T cells, activated CD8 + T cells, monocytes, activated dendritic cells, neutrophils, mast cells, and myeloid-derived suppressor cells
We calculated the enrichment score, which represents the level of immune cell infiltration, and generated a heatmap to visualize the relative abundance of each cell type (Figure 2A)
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder predominantly affecting motor neurons. It has a prevalence of 4.42 per 100,000 people worldwide, which increases by age until the age of 70–79 (Logroscino et al, 2010; Ingre et al, 2015; Xu et al, 2020). ALS most frequently involves spinal and bulbar muscles but even respiratory. ALS is essentially a sporadic disorder, with only ∼10% of cases involving a genetic link, and in most patients the etiology is unclear. ALS becomes progressively generalized and patients die about 3–4 years after disease onset (van Es et al, 2017). Detailed knowledge of ALS development can lead to more effective management at an early stage of disease
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