MicroRNA‐183‐5p regulates TAR DNA‐binding protein 43 neurotoxicity via SQSTM1/p62 in amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that selectively attacks motor neurons, and leads to progressive muscle weakness and death. A common pathological feature is the misfolding, aggregation, and cytoplasmic mislocalization of TAR DNA‐binding protein 43 (TDP‐43) proteins in more than 95% of ALS patients, suggesting a universal role TDP‐43 proteinopathy in ALS. Mutations in SQSTM1/p62 have been identified in familial and sporadic cases of ALS. MicroRNAs (miRNAs) are small non‐coding RNAs that post‐transcriptionally regulate their target genes. Emerging evidence indicates that miRNA dysregulation is associated with neuronal toxicity and mitochondrial dysfunction, and also plays a pivotal role in ALS pathogenesis. Here, we report the first evidence that miR‐183‐5p is aberrantly upregulated in spinal cords of patients with ALS. Using luciferase reporter assays and miR‐183‐5p agomirs, we demonstrate that miR‐183‐5p regulates the SQSTM1/p62 3′‐untranslated region to suppress expression. A miR‐183‐5p agomir attenuated SOSTM1/p62 expression and led to an increase in TDP‐43 protein levels in neuronal and non‐neuronal cells. In contrast, a miR‐183‐5p antagomir decreased TDP‐43 but increased SQSTM1/p62 protein levels. The antagomir repressed formation of stress granules and aggregated TDP43 protein in neuronal cells under stress‐induced conditions and protected against cytotoxicity. Knockdown of SQSTM1/p62 decreased total ubiquitination and increased TDP‐43 protein aggregation, indicating that SQSTM1/p62 may play a protective role in cells. In summary, our study reveals a novel mechanism of TDP‐43 proteinopathy mediated by the miR‐183‐5p and provides a molecular link between aberrant RNA processing and protein degradation, two major pillars in ALS pathogenesis. image