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  - 
TY  - JOUR
A1  - Lawatscheck, Robert
A1  - Aleksaite, Egle
A1  - Schenk, Jörg A.
A1  - Micheel, Burkhard
A1  - Jandrig, Burkhard
A1  - Holland, Gudrun
A1  - Sasnauskas, Kestutius
A1  - Gedvilaite, Alma
A1  - Ulrich, Rainer Günter
T1  - Chimeric polyomavirus-derived virus-like particles : the immunogenicity of an inserted peptide applied without adjuvant to mice depends on its insertion site and its flanking linker sequence
N2  - We inserted the sequence of the carcinoembryonic antigen-derived T cell epitope CAP-1-6D (CEA) into different positions of the hamster polyomavirus major capsid protein VP1. Independently from additional flanking linkers, yeast- expressed VP1 proteins harboring the CEA insertion between VP1 amino acid residues 80 and 89 (site 1) or 288 and 295 (site 4) or simultaneously at both positions assembled to chimeric virus-like particles (VLPs). BALB/c mice immunized with adjuvant-free VLPs developed VP1- and epitope-specific antibodies. The level of the CEA-specific antibody response was determined by the insertion site, the number of inserts, and the flanking linker. The strongest CEA-specific antibody response was observed in mice immunized with VP1 proteins harboring the CEA insert at site 1. Moreover, the CEA- specific antibodies in these mice were still detectable 6 mo after the final booster immunization. Our results indicate that hamster polyomavirus-derived VLPs represent a highly immunogenic carrier for foreign insertions that might be useful for clinical and therapeutic applications.
Y1  - 2007
UR  - http://www.liebertonline.com/vim
U6  - https://doi.org/10.1089/vim.2007.0023
SN  - 0882-8245
ER  -