Dysregulation of Muscle-Specific MicroRNAs as Common Pathogenic Feature Associated with Muscle Atrophy in ALS, SMA and SBMA: Evidence from Animal Models and Human Patients.

Eleonora Dalla Bella,Franco Salerno,Anna Venerando,Silvia Fenu,Silvia Bonanno,M Galbiati ,Stefania Marcuzzo,Viviana Pensato,Claudia Malacarne,Giuseppe Lauria,Renato Mantegazza,Monica Nizzardo,Lorenzo Maggi,Pia Bernasconi,Riccardo Masson,Cinzia Gellera,Eleonora Giagnorio,Davide Pareyson,Francesca Andreetta,Stefania Corti,Michela Taiana,Paola Cavalcante,Cinzia Cagnoli ,Angelo Poletti

doi:10.3390/ijms22115673

Abstract

Motor neuron diseases (MNDs) are neurodegenerative disorders characterized by upper and/or lower MN loss. MNDs include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). Despite variability in onset, progression, and genetics, they share a common skeletal muscle involvement, suggesting that it could be a primary site for MND pathogenesis. Due to the key role of muscle-specific microRNAs (myomiRs) in skeletal muscle development, by real-time PCR we investigated the expression of miR-206, miR-133a, miR-133b, and miR-1, and their target genes, in G93A-SOD1 ALS, Δ7SMA, and KI-SBMA mouse muscle during disease progression. Further, we analyzed their expression in serum of SOD1-mutated ALS, SMA, and SBMA patients, to demonstrate myomiR role as noninvasive biomarkers. Our data showed a dysregulation of myomiRs and their targets, in ALS, SMA, and SBMA mice, revealing a common pathogenic feature associated with muscle impairment. A similar myomiR signature was observed in patients’ sera. In particular, an up-regulation of miR-206 was identified in both mouse muscle and serum of human patients. Our overall findings highlight the role of myomiRs as promising biomarkers in ALS, SMA, and SBMA. Further investigations are needed to explore the potential of myomiRs as therapeutic targets for MND treatment.

Highlights

Motor neuron diseases (MNDs) are a heterogeneous group of rare disorders characterized by degeneration of motor neurons
G93A-superoxide dismutase 1 (SOD1) mice displayed an increase of miR-206 starting from week 8, corresponding to the presymptomatic phase, to week 18, suggesting that its overexpression is an early phenomenon appearing before disease symptoms become evident, and maintained during disease course; in ∆7SMA and AR113Q mice, miR-206 up-regulation was significant at symptomatic disease phase, corresponding to day 10 and week 40, respectively
Lower levels of this miRNA were found in G93A-SOD1 animals from week 8 to 18, and in AR113Q mice from week 14 to 40, whereas a significant miR-1 increase was observed at day 10 in ∆7SMA mice (** p < 0.01)

Summary

Introduction

Motor neuron diseases (MNDs) are a heterogeneous group of rare disorders characterized by degeneration of motor neurons. ALS is a progressive and fatal neurodegenerative disease affecting both upper and lower motor neurons of the motor cortex, brainstem, and spinal cord. Most ALS cases are sporadic (sALS), but 5–10% present familial inheritance (fALS), and 20% of these are due to mutations in the superoxide dismutase 1 (SOD1) gene, which acquires a toxic gain of function [4]. In both sALS and fALS, there is a variable loss of upper and lower motor neurons [5], resulting in a similar pathology [6]

Methods

Results

Discussion

Conclusion