Depletion of cognate charged transfer RNA causes translational frameshifting within the expanded CAG stretch in huntingtin.
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.
Department of Biochemistry and Biology, University of Potsdam, Karl-Liebknecht-Str. 24-25, 14476 Potsdam, Germany.
Hannah
H
Girstmair
Paul
P
Saffert
Sascha
S
Rode
Andreas
A
Czech
Gudrun
G
Holland
Norbert
N
Bannert
Zoya
Z
Ignatova
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018965:Frameshifting, Ribosomal / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D002479:Inclusion Bodies / Q000378:metabolism / Q000648:ultrastructure; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000648:ultrastructure; D010455:Peptides / Q000235:genetics; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D046249:Transfer RNA Aminoacylation / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C019529:polyalanine; C097188:polyglutamine