Abstract
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.
Highlights
Www.nature.com/scientificreports expression in fundamental cellular processes and, post-transcriptionally, in the translation levels of target mRNA transcripts[9]
A central role for autophagy in Amyotrophic lateral sclerosis (ALS) is well supported by the pathology of the disease, which commonly includes the accumulation of protein aggregates and swollen mitochondria in motor neurons of affected patients[26]
We observed significantly different expression levels between ALS patients and controls in 13 out of the 185 mRNAs included in the panel from the discovery phase (Fig. 1)
Summary
Www.nature.com/scientificreports expression in fundamental cellular processes and, post-transcriptionally, in the translation levels of target mRNA transcripts[9]. Deregulation of miRNA function is associated with numerous diseases[12], including ALS13,14. Oxidative stress and mitochondrial damage are key features of most neurodegenerative diseases[15,16], including ALS17, suggesting that mitochondrial dysfunction might contribute to motor neuron pathology[18,19]. Mitochondrial oxidative stress is responsible for mitochondrial DNA damage in spinal motor neurons of sporadic ALS patients[20]. A central role for autophagy in ALS is well supported by the pathology of the disease, which commonly includes the accumulation of protein aggregates and swollen mitochondria in motor neurons of affected patients[26]. We aimed to analyze the miRNA expression pattern in ALS serum and test the hypothesis that deregulation of some miRNA affects the mitochondrial physiology of neuronal cells
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