Huntington’s disease is a neurodegenerative disorder caused by mutations in the CAG trinucleotide repeats in exon 1 of the huntingtin (Htt) gene. This sequence encodes an expanded polyglutamine (polyQ) stretch in the N-terminal region of the mutant Htt (mHtt) protein. The expanded polyQ region is directly involved in aggregation and Htt-mediated cytotoxicity. However, the mechanisms by which polyQ-expanded Httex1 causes toxicity remain unclear. A recent study in our lab (1) identified that mutant Htt forms two different aggregates – early nascent and mature late aggregates. It has been found that cells with early inclusions have markers of stress: an increased mitochondrial membrane potential, increased levels of reactive oxygen species, and an increased risk of apoptosis. Inclusion formation progressively leads the cell into a quiescent state which correlates to a slower rate of death by necrosis. Another study (2) showed that the polyQ-expanded Httex1 is degraded more efficiently in cells lacking inclusions. Hence, we hypothesize that there is an unknown quality control mechanism which is responsible for clearing and sequestering nascent mHtt peptides emerging from ribosome in cells lacking inclusions. Using ribosomal capture, proteomics and CRISPR-Cas9 whole-genome screening we hope to understand early mediators of toxicity and also to investigate the nature of nascent Httex1’s interaction with the ribosome. We hope to find novel quality-control mechanisms operating at the translational level to reduce mHtt toxicity in Huntington’s disease.