Identification of Regulatory Factors and Prognostic Markers in Amyotrophic Lateral Sclerosis.

Ming Li,Dingding Shen,Jianwei Zhu,Hualin Sun,Wei Wang,Zehao Chen,Yuntian Shen,Yanan Ji,Qiong Cheng,Lilei Zhang,Chunyan Deng

doi:10.3390/antiox11020303

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle paralysis, which involves the degeneration of upper motor neurons (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord [1].amyotrophic lateral sclerosis (ALS) is the most common adult motor neuron disease, with an incidence rate of 2 cases per 100,000 people and a prevalence of 5.4 cases per 100,000 people [2]
We found that the similarity of differentially expressed genes (DEGs) between datasets on nerve tissue (Figure 1A) and the number of DEGs in nerve tissue in each dataset were higher than the corresponding values for lymphoid tissue and whole blood (Figure 1B)
To investigate the relationship between the DEGs and the occurrence and development of ALS, we performed Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and found that the up-regulated genes in the nerve tissue of ALS patients were mainly related to immunity and inflammation

Summary

Introduction

ALS is the most common adult motor neuron disease, with an incidence rate of 2 cases per 100,000 people and a prevalence of 5.4 cases per 100,000 people [2]. The mean age of onset of ALS is between 50 and 65 years. Death occurs because of respiratory failure within 2–3 years of onset [3]. Riluzole and edaravone are two drugs approved by the US Food and Drug Administration for ALS treatment. Riluzole is considered to reduce motor neuron damage by inhibiting glutamate release, while edaravone is considered to be a neuroprotective agent and free radical scavenger that reduces oxidative stress [5]

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