A018 Reduced ribosomal accuracy in Huntington disease

<h3></h3> Huntington disease (HD) is an inherited neurodegenerative disease. The stability of the proteome – proteostasis – is crucial for cellular integrity. Proteins are synthesized by ribosomes consisting of ribosomal proteins and catalytic active ribosomal-RNA (rRNA). rRNA is encoded by the rDNA and transcribed by the RNA-polymerase I transcription machinery (Pol-I). rRNA is modified at several sides. These modifications are crucial for ribosomal function. Enzymes are guided by small nucleolar RNAs (snoRNAs) to the sides of modification. Reanalysing small RNA seq data from human HD brain samples revealed that several snoRNAs are dysregulated. Therefore, we hypothesize that the loss of proteostasis in HD could be connected to ribosomal impairments. Using CUT&amp;TAG, we were able to establish an association of HTT to rDNA, among other things, suggesting a role of HTT in rDNA transcription. We also detected alterations in rRNA maturation. Moreover, the translational fidelity of ribosomes, isolated from patient cell lines, showed an increase in translational errors in a polyQ-length dependent manner. The proteome of R6/2 mouse (8 weeks old) brains showed accelerated protein unfolding, induced by increased temperature, as compared to matched controls. The proteome of the only mildly affected HdhQ111 mice (12 months old) did not show these changes. These findings correlate to others connected to a disturbed proteostasis. Taken together, our findings indicate a tight correlation of proteome instability and neurodegeneration (figure 1). The increased error rate in the translational process could help explaining the observed loss of proteostasis in Huntington’s disease.