Identification of Regulatory Factors and Prognostic Markers in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of motor neurons, leading to muscle atrophy, paralysis and even death. Immune disorder, redox imbalance, autophagy disorder, and iron homeostasis disorder have been shown to play critical roles in the pathogenesis of ALS. However, the exact pathogenic genes and the underlying mechanism of ALS remain unclear. The purpose of this study was to screen for pathogenic regulatory genes and prognostic markers in ALS using bioinformatics methods. We used Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene set enrichment analysis (GSEA), and expression regulation network analysis to investigate the function of differentially expressed genes in the nerve tissue, lymphoid tissue, and whole blood of patients with ALS. Our results showed that the up-regulated genes were mainly involved in immune regulation and inflammation, and the down-regulated genes were mainly involved in energy metabolism and redox processes. Eleven up-regulated transcription factors (CEBPB, CEBPD, STAT5A, STAT6, RUNX1, REL, SMAD3, GABPB2, FOXO1, PAX6, and FOXJ1) and one down-regulated transcription factor (NOG) in the nerve tissue of patients with ALS likely play important regulatory roles in the pathogenesis of ALS. Based on construction and evaluation of the ALS biomarker screening model, cluster analysis of the identified characteristic genes, univariate Cox proportional hazards regression analysis, and the random survival forest algorithm, we found that MAEA, TPST1, IFNGR2, and ALAS2 may be prognostic markers regarding the survival of ALS patients. High expression of MAEA, TPST1, and IFNGR2 and low expression of ALAS2 in ALS patients may be closely related to short survival of ALS patients. Taken together, our results indicate that immune disorders, inflammation, energy metabolism, and redox imbalance may be the important pathogenic factors of ALS. CEBPB, CEBPD, STAT5A, STAT6, RUNX1, REL, SMAD3, GABPB2, FOXO1, PAX6, FOXJ1, and NOG may be important regulatory factors linked to the pathogenesis of ALS. MAEA, TPST1, IFNGR2, and ALAS2 are potential important ALS prognostic markers. Our findings provide evidence on the pathogenesis of ALS, potential targets for the development of new drugs for ALS, and important markers for predicting ALS prognosis.

Integrated bioinformatics, network pharmacology, and artificial intelligence to predict the mechanism of celastrol against muscle atrophy caused by colorectal cancer

“…The proliferation of tumor cells results in the secretion of a large number of vesicles, including exosomes, which may play a broad regulatory role in the development of cancer cachexia (Rao et al, 2020). Celastrol has been reported in the past literature to have anticancer effects on colon cancer (Moreira et al, 2022), inhibit colorectal cancer by inducing apoptosis in colorectal cancer cells (Zhang H. et al, 2022), have significant inhibitory effects on colorectal cancer (Wang S. et al, 2019), have good therapeutic effects on muscle atrophy (Kitahata et al, 2022), resist muscle atrophy (Gwag et al, 2013), and induce muscle fiber preservation (Gwag et al, 2015). In our present study, we used bioinformatics to analyze the potential miRNA-mRNA regulatory network of colorectal cancer via exosomes to regulate muscle atrophy through network pharmacology and the AI AlphaFold2 in an attempt to elucidate the possible regulatory mechanisms of celastrol via the miRNA-mRNA regulatory network on colorectal cancerous muscle atrophy.…”

“…mRNA targets were obtained by online database analysis of DE miRNAs, and a regulatory network model diagram was established according to the principle of miRNA‒mRNA regulation, with 22 miRNAs and 44 mRNAs in the network. Of these, CEBPD has been reported to be a biomarker for amyotrophic lateral sclerosis ( Sun et al, 2022 ). BDNF can improve muscle atrophy by promoting nerve regeneration ( Yongguang et al, 2022 ) and is a target for skeletal muscle inflammation ( Aby et al, 2021 ).…”

Genetically engineered neural stem cells (NSCs) therapy for neurological diseases; state‐of‐the‐art

“…243,244 The destruction of upper and lower motor neurons (MNs) in the motor cortex, the brain stem nuclei, and the anterior horn of the spinal cord leads to advanced muscle weakness and wasting. 245 In 2001, Oosthuyse et al for the first time declared that reduced levels of VEGF have a correlation with ALS pathogenesis. 246 They found that VEGF165 could boost the viability of MNs throughout hypoxia by binding to VEGFR2 and neuropilin 1.…”

Inflammation: Roles in Skeletal Muscle Atrophy

“…Neuroinflammation is increasingly recognized as an important factor for cell-specific neurodegeneration in many central nervous system diseases, including ALS [ 148 ]. Upregulation of inflammatory factors has been observed in both ALS patients and animal models, and inflammatory factor levels are closely related to disease severity [ 149 ]. Astrocytes and microglia are two major sources of inflammatory mediators in the central nervous system.…”