Skeletal Muscle MicroRNAs as Key Players in the Pathogenesis of Amyotrophic Lateral Sclerosis.

Lorena Di Pietro,Camilla Bernardini,Wanda Lattanzi

doi:10.3390/ijms19051534

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, for which, to date, no effective treatment to ameliorate the clinical manifestations is available. The long-standing view of ALS as affecting only motor neurons has been challenged by the finding that the skeletal muscle plays an active role in the disease pathogenesis and can be a valuable target for therapeutic strategies. In recent years, non-coding RNAs, including microRNAs, have emerged as important molecules that play key roles in several cellular mechanisms involved in the pathogenic mechanisms underlying various human conditions. In this review, we summarize how the expression of some microRNAs is dysregulated in the skeletal muscle of ALS mouse models and patients. Shedding light on the mechanisms underlying microRNAs dysregulation in the skeletal muscle could clarify some of the processes involved in the pathogenesis of ALS and especially identify new promising therapeutic targets in patients.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, characterized by motor neuron degeneration, followed by muscle weakness, paralysis, and death
The aim of this review is to summarize how specific microRNAs are altered in the skeletal muscle of ALS mouse models and patients, and how this dysregulation could participate and interfere with the balance between denervation/re-innervation and muscle regeneration/atrophy processes
They focused on miR-23a, which was dysregulated in the mouse model [25], and demonstrated that it repressed PGC-1α translation acting on the 3 untranslated region (UTR) [28]. They demonstrated that transgenic mice over-expressing miR-23a had a reduction in PGC-1α, cytochrome-b, and COXIV protein levels [28], proteins involved in mitochondrial biogenesis and function, fusion, and electron transport chain activity. These results showed that the mitochondrial dysfunction observed in the skeletal muscle of ALS patients was associated with a reduction in PGC-1α signaling networks; the increase in several microRNAs could be potentially implicated in skeletal muscle and neuromuscular junction regeneration

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, characterized by motor neuron degeneration, followed by muscle weakness, paralysis, and death. ALS is caused by a combination of genetic, epigenetic, and environmental risk factors and patients undergo a very variable disease progression, with death usually occurring because of respiratory failure in 3–5 years. Over 90% cases of ALS are sporadic, while the remaining 5–10% show a familial inheritance. More than 20 genes have been identified whose mutations are involved in the development of the disease. Mutations in C9orf, SOD1, TARDBP, UBQLN2, and FUS genes are the most frequent. No effective treatment to remarkably ameliorate the clinical manifestations is available. For a long time riluzole has remained the only treatment, offering modest survival benefit for ALS patients. Edaravone leads to a reduction of ALSFRS-R (ALS Functional Rating Scale Revised) score, while, to date, there are no data indicating any longer-term effect on patients’ safety and survival [1]

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