Williams AH, Valdez G, Moresi V, Qi X, McAnally J, Elliott JL, Bassel-Duby R, Sanes JR, Olson EN.
MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice.
Science. 2009 Dec 11;326(5959):1549-54.
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The Olson group is a pioneer in the field of microRNA function in muscle cells. Here, the authors provide compelling evidence that miR-206, a skeletal muscle-specific “myomiR,” functions in a complex regulatory pathway to regulate ALS pathology in mice. The strength of this paper relies on the use of different mouse models, including miR-206 knockouts, to characterize the signaling pathway in vivo.
To obtain insights into the mechanism(s) involved in muscle degeneration in ALS, the authors performed a microRNA array from ALS mice, which harbor the familial SOD1 G93A mutation. MiR-206 was the most significantly changed (upregulated) miRNA in this screen. It is interesting to note that other myomiRs, including miR-1, miR-133b, and miR-133a were, albeit at weaker levels, downregulated in the array; however, the authors could confirm by quantitative PCR the upregulation of miR-206 and miR-133b (which are co-expressed from the same transcript) in the diseased mice. MiR-206 upregulation coincided with denervation and ALS pathology in the mutant mice. To make a long story short, the group identified both upstream (MyoD) and downstream (HDAC4, FGFBP1) effectors of the miR-206 network in vivo. Overall, an elegant study!
This work contributes significantly to our knowledge with regard to microRNA function in health and disease. Although individual microRNAs can target up to several hundred genes, it’s important to keep in mind that the observed pathological effects in vivo often result from the abnormal fine-tuning of a limited number of "key" genes. With regard to the current study, the effects of miR-206 in reinnervation could be explained, in most part, by the misregulation of HDAC4 (a miR-206 target). One could hypothesize that this mode of “targeted” pathological regulation could function in Alzheimer disease brain, where, for instance, miR-29 could contribute to plaque load by modulating BACE1 regulation.
Although well structured, this study does not, in my opinion, address the primary cause of motor neuron degeneration in ALS (mice or humans). An interesting follow-up study would be to look for changes in microRNA expression in the CNS. In this sense, this study lacks validation of microRNA (and target gene) expression in humans. Notably, the miR-206/miR-133b locus was originally described as a synapse-associated non-coding RNA (7H4)(see current study). Interestingly, it has been documented that miR-206 can become overexpressed in the brain after cellular insult (Jeyaseelan et al., 2008; Zhang and Pan, 2009). Also, one study associates miR-206 with schizophrenia (Hansen et al., 2007). In the current study, axonal regeneration seemed unaffected in the miR-206 knockout mice. Clearly, future studies are needed to elucidate the role of microRNAs, particularly miR-206, in both neuronal and muscle loss.