Defective RNA metabolism is an emerging mechanism involved in ALS pathogenesis and possibly in other neurodegenerative disorders. Here, we show that microRNA (miRNA) activity is essential for long-term survival of postmitotic spinal motor neurons (SMNs) in vivo. Thus, mice that do not process miRNA in SMNs exhibit hallmarks of spinal muscular atrophy (SMA), including sclerosis of the spinal cord ventral horns, aberrant end plate architecture, and myofiber atrophy with signs of denervation. Furthermore, a neurofilament heavy subunit previously implicated in motor neuron degeneration is specifically up-regulated in miRNA-deficient SMNs. We demonstrate that the heavy neurofilament subunit is a target of miR-9, a miRNA that is specifically down-regulated in a genetic model of SMA. These data provide evidence for miRNA function in SMN diseases and emphasize the potential role of miR-9–based regulatory mechanisms in adult neurons and neurodegenerative states.

MicroRNAs (miRNAs) were shown to be important for pancreas development, yet their roles in differentiated β‐cells remain unclear. Here, we show that miRNA inactivation in β‐cells of adult mice results in a striking diabetic phenotype. While islet architecture is intact and differentiation markers are maintained, Dicer1‐deficient β‐cells show a dramatic decrease in insulin content and insulin mRNA. As a consequence of the change in insulin content, the animals become diabetic. We provide evidence for involvement of a set of miRNAs in regulating insulin synthesis. The specific knockdown of miR‐24, miR‐26, miR‐182 or miR‐148 in cultured β‐cells or in isolated primary islets downregulates insulin promoter activity and insulin mRNA levels. Further, miRNA‐dependent regulation of insulin expression is associated with upregulation of transcriptional repressors, including Bhlhe22 and Sox6. Thus, miRNAs in the adult pancreas act in a new network that reinforces insulin expression by reducing the expression of insulin transcriptional repressors. There is a [Have you seen?][1] (March 2011) associated with this Article. [1]: http://dx.doi.org/10.1038/emboj.2011.31

Interest in RNA dysfunction in amyotrophic lateral sclerosis (ALS) recently aroused upon discovering causative mutations in RNA‐binding protein genes. Here, we show that extensive down‐regulation of miRNA levels is a common molecular denominator for multiple forms of human ALS. We further demonstrate that pathogenic ALS‐causing mutations are sufficient to inhibit miRNA biogenesis at the Dicing step. Abnormalities of the stress response are involved in the pathogenesis of neurodegeneration, including ALS. Accordingly, we describe a novel mechanism for modulating microRNA biogenesis under stress, involving stress granule formation and re‐organization of DICER and AGO2 protein interactions with their partners. In line with this observation, enhancing DICER activity by a small molecule, enoxacin, is beneficial for neuromuscular function in two independent ALS mouse models. Characterizing miRNA biogenesis downstream of the stress response ties seemingly disparate pathways in neurodegeneration and further suggests that DICER and miRNAs affect neuronal integrity and are possible therapeutic targets. Synopsis Amyotrophic Lateral Sclerosis‐causing mutations affect DICER complex activity and lead to altered miRNA biogenesis. Reduction in miRNA levels unifies genetically unrelated forms of human ALS. miRNA biogenesis is attenuated by cellular stress or by ALS proteins, TDP‐43, FUS or SOD1. Stress granule protein interactions with DICER complex underlie reduced activity. Enoxacin, a DICER agonist, mitigates miRNA biogenesis defect and neuromuscular deterioration in models of ALS.

MicroRNAs (miRNAs) are a family of small, non‐coding RNAs, which provides broad silencing activity of mRNA targets in a sequence‐dependent fashion. This review explores the hypothesis that the miRNA machinery is intimately linked with the cellular stress pathway and apparatus. Stress signaling potentially alters the function of the miRNA‐bioprocessing core components and decompensates regulation. In addition, dysregulation of miRNA activity renders the cell more prone to stress and emerges as a new pathway for age‐related insults and diseases, such as neurodegeneration. The EMBO Journal (2014) 33: 1428–1437