Abstract: Triosephosphate isomerase deficiency (TPI Df) is a devastating childhood degenerative disease for which there are currently no treatments. Pathogenesis of this disease is driven by mutations that destabilize the TPI protein. A genome-wide RNAi screen in Drosophila to identify regulators of TPI stability is described. The screen identified 25 proteins that are critical to TPI stability, each of which has a human ortholog. Methods of promoting TPI protein stability and treating TPI Df in a subject by administering a therapeutically effective amount of an agent that inhibits expression or activity of one of the identified regulators are described. Also described is a method for the identification of agents capable of promoting stability of mutant TPI. Methods for treating a subject who has TPI Df by administering an agent that promotes stability of mutant TPI is also described.