Molecular Mechanism For Tau Misfolding Inhibited By Protein Disulfide Isomerase

Alzheimer disease is a progressive and irreversible neurodegenerative disease. The morphology of Alzheimer disease includes neurofibrillary tangles (NFTs) and senile plaques. NFTs are composed of bundles of filaments formed by microtubule associated protein Tau. Protein disulfide isomerase (PDI) is a member of the thioredoxin superfamily, and there are some reports that PDI prevents the neurotoxicity associated with ER stress and misfolding. However the mechanism how PDI can regulate the misfolding of Tau is unclear. Herein, by using recombinant human Tau fragment Tau244-372, we have investigated the effect of human PDI on the aggregation of Tau. By using thioflavin T binding, turbidity assays, and transmission electron microscopy, we have found that PDI can inhibit fibril formation of human Tau fragment Tau244-372, and the inhibitory effect is dependent on both the concentration and domains of PDI. We have found that the domain a of PDI play an important role in inhibiting Tau244-372fibril formation. However the addition of PDI bb’x domain had no significant suppressing effect on Tau aggregation. Higher concentrations of PDI induced wild-type Tau244-372to form fewer and shorter filaments. The FRET measurement revealed that PDI interacts with Tau in living SH-SY5Y cells. Besides we have obtained thermodynamic parameters for the interaction between human Tau fragment Tau244-372and human PDI by using isothermal titration calorimetry. Our results provide new insight into the role of PDI in protecting ER from the harmful effects of misfolded proteins accumulated in Alzheimer disease.