caused by protein aggregates and soluble oligomers by disassembling these structures and recovering natively-folded proteins. The yeast protein disaggregase, Hsp104, disassembles disease-associated protein aggregates and soluble oligomers to suppress toxicity. Hsp104 has a yeast mitochondrial homologue, namely Hsp78. I targeted mitochondrial (mt) Hsp78 (mtHsp78) to the cytoplasm (cHsp78) and potentiated its activity via homologous mutations that nonselectively potentiated Hsp104. Three cHsp78 variants selectively rescue a-synuclein (aSyn), FUS, or TDP-43 toxicity in yeast. Three different mtHsp78 variants rescue aSyn toxicity in yeast without affecting cytoplasmic aSyn aggregation. We are exploring the mechanism of rescue for each of these variants. Additionally, we are interested in the possibility of targeting non-native disaggregases to other organelle such as the endoplasmic reticulum. The results further our understanding of the substrate and compartment specific demands of protein disaggregases in higher eukaryotes. How post-translational modifications alter the structures and interactions of proteins is of great interest for understanding proteomic changes during aging and disease. Oxidative modifications of the long-lived cysteine-rich lens g-crystallins are strongly associated with their aggregation into light-scattering structures that result in cataracts -the leading cause of age-related vision loss. How oxidation leads to aggregation is not well understood. Our previous computational and experimental work showed that formation of a particular non-native intramolecular disulfide bond in cataract-associated W42Q/R human gD-crystallin variants trapped a partially unfolded intermediate state prone to aggregation. Surprisingly, it also revealed that the wild-type protein was able to specifically promote aggregation of these variants without itself aggregating. The search for a biochemical mechanism behind this unprecedented ''inverse-prion'' interaction has now revealed that human gD-crystallin exhibits oxidoreductase activity. This activity depended on formation of a specific internal disulfide bond, which we mapped by LC/MS/MS and by comprehensive Cys mutagenesis. All-atom Monte-Carlo simulations with a statistical potential revealed conformational strain upon formation of this disulfide, which was confirmed by differential scanning flourometry. Disulfide exchange occurred among purified gD-crystallin molecules in solution. Both the Cys-oxidized (disulfide-bonded) wild-type protein and the destabilized (Trpoxidation mimicking) W42Q variant were highly soluble at physiological temperature and pH. When the two were mixed, however, the disulfide bond transferred from the WT to the mutant. Once oxidized, the mutant became aggregation-prone, its insolubilization helping drive the disulfide transfer. Destabilized or damaged gcrystallins may act as oxidation sinks in the lens, forming light-scattering aggregates as a consequence. There is evidence that human gD-crystallin's newly found oxidoreductase activity i...