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Ageing

MicroRNA tunes ageing pathway in flies

Nature Reviews Genetics volume 13, pages 222–223 (2012)Cite this article

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Following the observation that a mutation in an miRNA-processing gene leads to a shortened lifespan and late-onset brain neurodegeneration in Drosophila melanogaster, the authors set out to identify fly miRNAs that have age-modulated expression patterns in the adult brain. The expression of one such miRNA, miR-34, was very low during early development, but it increased with age. Null miR-34 mutants were normal as young adults but showed a striking decline in viability and locomotion, as well as morphological signs of neural deterioration at later time points, suggesting that miR-34 affects lifespan as well as adult brain integrity. These phenotypes are consistent with the finding that the brains of miR-34 mutants, but not wild-type flies, show transcriptional profiles that are associated with accelerated brain ageing. Experimentally increasing miR-34 levels gives opposite ageing phenotypes from loss-of-function mutations: these flies are protected from neurodegeneration and have an extended median lifespan.

miR-34 is predicted to target binding sites in the 3′ untranslated region (UTR) of the Ecdysone-induced protein 74EF (Eip74EF) mRNA, which encodes a transcription factor in the steroid hormone signalling pathway. Expression of one Eip74EF isoform, Eip74EFA, increases in late adulthood when miR-34 is absent; the increased miR-34 expression that is observed in normal adults could therefore serve to silence Eip74EFA expression during this period. The causal link between miR-34 function, Eip74EFA levels and ageing phenotypes was established by, among other methods, showing that Eip74EFA protein expression is elevated in animals in which Eip74EFA lacks miR-34-binding sites, leading to neurodegeneration phenotypes and poor survival.

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References

ORIGINAL RESEARCH PAPER

  1. Liu, N. et al. The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila. Nature 15 Feb 2012 (doi:10.1038/nature10810)

FURTHER READING

  1. Lessing, D & Bonini, N. M. Maintaining the brain: insight into human neurodegeneration from Drosophila melanogaster mutants. Nature Rev. Genet. 10, 359–370 (2009)

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  1. Tanita Casci
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Casci, T. MicroRNA tunes ageing pathway in flies. Nat Rev Genet 13, 222–223 (2012). https://doi.org/10.1038/nrg3205

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