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Neurodegenerative diseases

RNA interference meets brain disease

Nature Reviews Neuroscience volume 5, page 10 (2004)Cite this article

RNAi is based on a highly conserved defense mechanism in which short, double-stranded RNA fragments are enzymatically snipped from foreign genetic material and subsequently disrupt the translation of their messenger RNA of origin. DiLeone et al. designed hairpin-shaped RNA fragments to specifically target two unique 24-nucleotide stretches of the tyrosine hydroxylase mRNA. These fragments were co-expressed with enhanced green fluorescent protein (EGFP) in an adeno-associated viral vector, which was then injected into the midbrain of adult mice.

Twelve days after injections to the substantia nigra pars compacta, immunostaining and quantitative real-time reverse transcription-polymerase chain reaction showed that expression of tyrosine hydroxylase was markedly reduced in infected dopamine neurons (that is, those neurons positive for both EGFP and dopa-decarboxylase, a marker of dopamine neurons). This attenuation of expression persisted for at least 50 days. Levels of tyrosine hydroxylase in regions of the nucleus accumbens innervated by infected midbrain neurons were also reduced. By contrast, high levels of tyrosine hydroxylase expression were maintained in control neurons infected with a vector containing 'scrambled', non-tyrosine hydroxylase-specific short RNA fragments.

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References

ORIGINAL RESEARCH PAPER

  1. Hommel, J. D. et al. Local gene knockdown in the brain using viral-mediated RNA interference. Nature Med. 9, 1539–1544 (2003)

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FURTHER READING

  1. Opalinska, J. B. & Gewirtz, A. M. Nucleic-acid therapeutics: basic principles and recent applications. Nature Rev. Drug Discov. 1, 503–514 (2002)

    Article  CAS  Google Scholar 

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Authors
  1. Suzanne Farley
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Farley, S. RNA interference meets brain disease. Nat Rev Neurosci 5, 10 (2004). https://doi.org/10.1038/nrn1318

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  • DOI: https://doi.org/10.1038/nrn1318

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