Establishing mRNA and microRNA interactions driving disease heterogeneity in amyotrophic lateral sclerosis patient survival

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, associated with the degeneration of both upper and lower motor neurons of the motor cortex, brainstem and spinal cord. Death in most patients results from respiratory failure within 3-4 years from symptom onset. However, due to disease heterogeneity some individuals survive only months from symptom onset while others live for several years. Identifying specific biomarkers that aid in establishing disease prognosis, particularly in terms of predicting disease progression, will help our understanding of ALS pathophysiology and could be used to monitor a patient’s response to drugs and therapeutic agents. Transcriptomic profiling technologies are continually evolving, enabling us to identify key gene changes in biological processes associated with disease. MicroRNAs (miRNAs) are small non-coding RNAs typically associated with regulating gene expression, by degrading mRNA or reducing levels of gene expression. Being able to associate gene expression changes with corresponding miRNA changes would help to distinguish a more complex biomarker signature enabling us to address key challenges associated with complex diseases such as ALS. The present study aimed to investigate the transcriptomic profile (mRNA and miRNA) of lymphoblastoid cell lines (LCLs) from ALS patients to identify key signatures that are distinguishable in those patients who suffered a short disease duration (< 12 months) (n = 22) compared to those that had a longer disease duration (>6 years) (n = 20). Transcriptional profiling of miRNA-mRNA interactions from LCL’s in ALS patients revealed differential expression of genes involved in cell cycle, DNA damage and RNA processing in patients with longer survival from disease onset compared to those with short survival. Understanding these particular miRNA-mRNA interactions and the pathways in which they are involved may help to distinguish potential therapeutic targets that could exert neuroprotective effects to prolong the life expectancy of ALS patients.