TY  - JOUR
A1  - Girstmair, Hannah
A1  - Saffert, Paul
A1  - Rode, Sascha
A1  - Czech, Andreas
A1  - Holland, Gudrun
A1  - Bannert, Norbert
A1  - Ignatova, Zoya
T1  - Depletion of Cognate Charged Transfer RNA Causes Translational Frameshifting within the Expanded CAG Stretch in Huntingtin
JF  - Cell reports
N2  - Huntington disease (HD), a dominantly inherited neurodegenerative disorder caused by the expansion of a CAG-encoded polyglutamine (polyQ) repeat in huntingtin (Htt), displays a highly heterogeneous etiopathology and disease onset. Here, we show that the translation of expanded CAG repeats in mutant Htt exon 1 leads to a depletion of charged glutaminyl-transfer RNA (tRNA) Gln-CUG that pairs exclusively to the CAG codon. This results in translational frameshifting and the generation of various transframe-encoded species that differently modulate the conformational switch to nucleate fibrillization of the parental polyQ protein. Intriguingly, the frameshifting frequency varies strongly among different cell lines and is higher in cells with intrinsically lower concentrations of tRNA Gln-CUG. The concentration of tRNA Gln-CUG also differs among different brain areas in the mouse. We propose that translational frameshifting may act as a significant disease modifier that contributes to the cell-selective neurotoxicity and disease course heterogeneity of HD on both cellular and individual levels.
Y1  - 2013
U6  - https://doi.org/10.1016/j.celrep.2012.12.019
SN  - 2211-1247
VL  - 3
IS  - 1
SP  - 148
EP  - 159
PB  - Cell Press
CY  - Cambridge
ER  -