In this study, we have firstly proved the molecular interaction between TPPP and PrP, and subsequently identified the segments of TPPP spanning residues 100�C219 and the segments of PrP spanning residues 106�C126 as the interacting regions for those two proteins. Disfunction of microtubule is repeatedly described in some neurodegenerative diseases, including human and animal prion diseases. Our previous studies have Staurosporine PKC inhibitor confirmed that PrP is able to binding with cellular tubulin through its N-terminus and WT-PrP does not influence the formation of microtubule from tubulin in vitro and the normal microtubule structure in cultured cells. On the other hand, changes of PrP sequences, e.g. fCJD related PrP mutants with extra octarepeats insertions, and changes of subcellular position of PrP in cells, e.g. accumulation of cytosolic PrP in cytoplasm, result in not only strong inhibition on microtubule assembly in vitro, but also apparent disruption of microtubule structures in cells, which are largely related with the final phenomenon of cell apoptosis. Those abnormalities of cellular microtubule structures are believed to be related with the molecular interaction between PrP and tubulin, as the octarepeat-insertional PrPs and CytoPrP show apparently binding capacities with tubulin, even that the octarepeat-insertional PrPs possess stronger binding activities. Although expressions of TPPP and WT-PrP, separately or together, affects neither the microtubule structure nor cell viability, our data here have provided the evidences that presence of TPPP does antagonize the disruptive effect on cellular microtubule structure and the cytotoxicity of cytosolic PrP. It may suggest that TPPP, besides its function as an agent for dynamic stabilization of microtubular ultrastructures, works as a protective factor for cells against the damage effect of the accumulation of abnormal CytoPrP. Through the molecular interaction, TPPP shows apparent enhancement on the aggregation of the full-length recombinant PrP in vitro and DAPT Gamma-secretase inhibitor fibril formation of synthetical peptide PrP106�C126. Those phenomena seem to be more remarkable in the preparations of C-terminal constructs of TPPP , which contain the region for interacting with PrP. It has been described that in addition to the full-length TPPP , there are two shorter paralogs, TPPP2/p18 and TPPP3/p20, in the human TPPP group, which lack of the unfolded N-terminal tail. Study has reported that TPPP3/p20 displays more extensive microtubule-binding activity than TPPP/ p25. Those data, taking together with our data in this study, highlight that the C-terminus of TPPP is more active region for interacting with other biologically functional agents. Segment PrP106�C126 is an active domain of PrP, showing some PrPSc-like characteristics and a notable toxicity on neurons.