Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease for which the pathophysiological mechanisms of motor neuron loss are not precisely clarified. Environmental and epigenetic mechanisms such as microRNAs (miRNAs) could have a role in disease progression. We studied the expression pattern of miRNAs in ALS serum from 60 patients and 29 healthy controls. We also analyzed how deregulated miRNAs found in serum affected cellular pathways such as apoptosis, autophagy and mitochondrial physiology in SH-SY5Y cells. We found that miR-335-5p was downregulated in ALS serum. SH-SY5Y cells were transfected with a specific inhibitor of miR-335-5p and showed abnormal mitochondrial morphology, with an increment of reactive species of oxygen and superoxide dismutase activity. Pro-apoptotic caspases-3 and 7 also showed an increased activity in transfected cells. The downregulation of miR-335-5p, which has an effect on mitophagy, autophagy and apoptosis in SH-SY5Y neuronal cells could have a role in the motor neuron loss observed in ALS. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. It is classically characterized by weakness and atrophy due to loss of lower motor neurons in the brainstem and spinal cord and loss of upper motor neurons in the motor cortex 1. Degeneration, however, is now considered to be more widespread and not restricted to the motor system. Up to 50% of patients show evidence of behavioral and cognitive dysfunction, suggesting pathologic changes involving the frontal and temporal cortex, and sometimes fulfilling diagnostic criteria of frontotemporal dementia (FTD). These disorders are now considered to be manifestations within the clinicopathological spectrum of an underlying mechanism of neurodegeneration 2,3. The molecular pathogenic mechanism of ALS onset and progression is not completely known. Environmental factors have been described as potential contributors to neurodegeneration and ALS progression, but none have proven to be causative 4,5. Mutations in more than 25 genes have been implicated in familial (fALS) and sporadic ALS (sALS) forms 6 , suggesting a wide heterogeneity in the molecular bases of the disease. Several ALS-causing genes encode proteins involved in RNA metabolism processes, such as RNA transcription, splicing, mRNA transport and microRNAs (miRNAs) biogenesis 7. Dysfunction of these mechanisms is not exclusive and may lead to diverse cellular abnormalities. Epigenetic mechanisms, such as miRNAs, could regulate the expression of genes involved in common cellular pathways that are disrupted in ALS and therefore have an impact on ALS phenotype 8. MiRNAs are small, non-coding RNA molecules of approximately 22 nucleotides that regulate gene

Objective To analyze the microRNA profile in serum of patients with Adult Onset Pompe disease (AOPD). Methods We analyzed the expression of 185 microRNAs in serum of 15 AOPD patients and five controls using microRNA PCR Panels. The expression levels of microRNAs that were deregulated were further studied in 35 AOPD patients and 10 controls using Real‐Time PCR. Additionally, the skeletal muscle expression of microRNAs which showed significant increase levels in serum samples was also studied. Correlations between microRNA serum levels and muscle function test, spirometry, and quantitative muscle MRI were performed (these data correspond to the study NCT01914536 at ClinicalTrials.gov). Results We identified 14 microRNAs that showed different expression levels in serum samples of AOPD patients compared to controls. We validated these results in a larger cohort of patients and we found increased levels of three microRNAs, the so called dystromirs: miR‐1‐3p, miR‐133a‐3p, and miR‐206. These microRNAs are involved in muscle regeneration and the expression of these was increased in patients' muscle biopsies. Significant correlations between microRNA levels and muscle function test were found. Interpretation Serum expression levels of dystromirs may represent additional biomarkers for the follow‐up of AOPD patients.