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Common pathological features of amyotrophic lateral sclerosis (ALS) include cytoplasmic aggregation of several RNA-binding proteins. Out of these RNA-binding proteins, TDP-43, FUS/TLS and RGNEF have been shown to co-aggregate with one another within motor neurons of sporadic ALS (sALS) patients, suggesting that there may be a common regulatory network disrupted. MiRNAs have been a recent focus in ALS research as they have been identified to be globally down-regulated in the spinal cord of ALS patients. The objective of this study was to identify if there are miRNA(s) dysregulated in sALS that are responsible for regulating the TDP-43, FUS/TLS and RGNEF network. In this study, we identify miR-194 and miR-b2122 to be significantly down-regulated in sALS patients, and were predicted to regulate  TARDBP ,  FUS/TLS  and  RGNEF  expression. Reporter gene assays and RT-qPCR revealed that miR-b2122 down-regulates the reporter gene through direct interactions with either the  TARDBP ,  FUS/TLS , or  RGNEF  3’UTR, while miR-194 down-regulates firefly expression when it contained either the  TARDBP  or  FUS/TLS  3’UTR. Further, we showed that miR-b2122 regulates endogenous expression of all three of these genes in a neuronal-derived cell line. Also, an ALS-associated mutation in the  FUS/TLS  3’UTR ablates the ability of miR-b2122 to regulate reporter gene linked to  FUS/TLS  3’UTR, and sALS samples which showed a down-regulation in miR-b2122 also showed an increase in FUS/TLS protein expression. Overall, we have identified a novel miRNA that is down-regulated in sALS that appears to be a central regulator of disease-related RNA-binding proteins, and thus its dysregulation likely contributes to TDP-43, FUS/TLS and RGNEF pathogenesis in sALS.   Electronic supplementary material  The online version of this article (doi: 10.1186/s13041-017-0326-7) contains supplementary material, which is available to authorized users.

Novel miR-b2122 regulates several ALS-related RNA-binding proteins