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Triosephosphate isomerase (TPI) deficiency (Df) is a rare recessive metabolic disorder that manifests as hemolytic anemia, locomotor impairment, and progressive neurodegeneration. Research suggests that TPI Df mutations, including the “common” TPIE105Dmutation, result in reduced TPI protein stability that appears to underlie disease pathogenesis. Drosophila with the recessive TPIsugarkill allele (a.k.a. sgk or M81T) exhibit progressive locomotor impairment, neuromuscular impairment and reduced longevity, modeling the human disorder. TPIsugarkill produces a functional protein that is degraded by the proteasome. Molecular chaperones, such as Hsp70 and Hsp90, have been shown to contribute to the regulation of TPIsugarkill degradation. In addition, stabilizing the mutant protein through chaperone modulation results in improved TPI deficiency phenotypes. To identify additional regulators of TPIsugarkill degradation, we performed a genome-wide RNAi screen that targeted known and predicted quality control proteins in the cell to identify novel factors that modulate TPIsugarkill turnover. Of the 430 proteins screened, 25 regulators of TPIsugarkill were identified. Interestingly, 10 proteins identified were novel, previously undescribed Drosophila proteins. Proteins involved in co-translational protein quality control and ribosome function were also isolated in the screen, suggesting that TPIsugarkill may undergo co-translational selection for polyubiquitination and proteasomal degradation as a nascent polypeptide. The proteins identified in this study may reveal novel pathways for the degradation of a functional, cytosolic protein by the ubiquitin proteasome system and define therapeutic pathways for TPI Df and other biomedically important diseases.