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Depletion of cognate charged transfer RNA causes translational frameshifting within the expanded CAG stretch in

Hannah Girstmair1, Paul Saffert, Sascha Rode

  • 1Department of Biochemistry and Biology, University of Potsdam, Karl-Liebknecht-Str. 24-25, 14476 Potsdam, Germany.

Cell Reports
|January 29, 2013
PubMed

Insights

Huntington disease (HD) involves CAG repeat expansion in huntingtin (Htt). This leads to a depletion of a specific transfer RNA (tRNA), causing translational frameshifting and contributing to HD

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Huntington disease (HD) is a dominantly inherited neurodegenerative disorder.
  • It is caused by the expansion of CAG repeats in the huntingtin (Htt) gene.
  • HD exhibits significant heterogeneity in its pathology and onset.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying Huntington disease heterogeneity.
  • To explore the role of tRNA depletion and translational frameshifting in HD pathogenesis.

Main Methods:

  • Analyzing the translation of expanded CAG repeats in mutant Htt exon 1.
  • Measuring charged glutaminyl-transfer RNA (tRNA(Gln-CUG)) concentrations.
  • Assessing translational frameshifting frequency in different cell lines and mouse brain areas.

Main Results:

  • Expanded CAG repeats in Htt lead to depletion of tRNA(Gln-CUG).
  • This depletion causes translational frameshifting, generating various transframe-encoded Htt species.
  • Frameshifting frequency correlates with tRNA(Gln-CUG) levels and varies across cell lines and brain regions.

Conclusions:

  • Translational frameshifting due to tRNA depletion is a novel mechanism in HD.
  • This process contributes to the cell-selective neurotoxicity and heterogeneous disease course observed in Huntington disease.
  • tRNA(Gln-CUG) levels may act as a significant disease modifier in HD.

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