Expression of microRNAs in human post-mortem amyotrophic lateral sclerosis spinal cords provides insight into disease mechanisms

Abstract

Amyotrophic lateral sclerosis is a late-onset and terminal neurodegenerative disease. The majority of cases are sporadic with unknown causes and only a small number of cases are genetically linked. Recent evidence suggests that post-transcriptional regulation and epigenetic mechanisms, such as microRNAs, underlie the onset and progression of neurodegenerative disorders; therefore, altered microRNA expression may result in the dysregulation of key genes and biological pathways that contribute to the development of sporadic amyotrophic lateral sclerosis. Using systems biology analyses on postmortem human spinal cord tissue, we identified dysregulated mature microRNAs and their potential targets previously implicated in functional process and pathways associated with the pathogenesis of ALS. Furthermore, we report a global reduction of mature microRNAs, alterations in microRNA processing, and support for a role of the nucleotide binding protein, TAR DNA binding protein 43, in regulating sporadic amyotrophic lateral sclerosis-associated microRNAs, thereby offering a potential underlying mechanism for sporadic amyotrophic lateral sclerosis.

ALS and FTD: an epigenetic perspective

“…Postmortem human spinal cord tissues from ALS subjects were assessed to identify aberrantly regulated microRNAs [55]. Expression and systems biology analyses revealed that mature miRNAs are globally reduced and miRNA processing is altered.…”

“…For example, miR-206 was consistently altered during the course disease in SOD1 -Gly93Ala mice and increased in the circulation of a small cohort of ALS patients [173]. Furthermore, exploring therapeutic strategies targeting pathogenic miRNAs in ALS is further supported by the recent report on aberrantly regulated miRNAS in sporadic ALS discussed above [55]. Manipulating miRNAs has the advantage to alter multiple gene targets simultaneously using a single drug, but the disadvantage of non-specific binding to other miRNAs resulting in deleterious off-target effects.…”

Dysregulation of microRNA biogenesis machinery and microRNA/RNA ratio in skeletal muscle of amyotrophic lateral sclerosis mice

“…The identification of miRNAs has enhanced our understanding of transcriptional and translational regulation, opening new avenues for investigating molecular mechanisms contributing to numerous diseases. Of particular interest are diseases associated with perturbations in RNA processing, such as amyotrophic lateral sclerosis (ALS) …”

“…A large number of miRNAs are known to be dysregulated in various ALS tissues, with a global downregulation of miRNAs observed in motor neurons of patients with ALS . How these dysregulated miRNAs influence the disease onset, progression, and severity still requires experimental validation.…”

“…Of particular interest are diseases associated with perturbations in RNA processing, such as amyotrophic lateral sclerosis (ALS). [9][10][11] A large number of miRNAs are known to be dysregulated in various ALS tissues, [9][10][11][12][13][14][15][16] with a global downregulation of miRNAs observed in motor neurons of patients with ALS. 17 How these dysregulated miRNAs influence the disease onset, progression, and severity still requires experimental validation.…”