PROJECT SUMMARY The primary objective of the Macromolecular and Cellular Structure Core is to provide cutting edge, innovative platforms for structural characterization responsive to needs and discoveries of the U54 FTD Center without Walls. The long-term goal of this FTD Center without Walls is to understand the overall metabolism of tau, how it is stabilized by chaperones and cochaperones and how it is channeled for degradation by the lysosome. This core will use the latest methodologies in cryoEM to determine atomic resolution cryoEM structures of relevant proteins and protein complexes as defined in Projects 1, 2 and to provide a cellular context for tau lysosomal degradation via cryoEM-Tomography. The high-resolution studies will be enabled via the expression and in vitro reconstitution of critical protein-protein complexes and novel cryoEM grid technologies developed by the Agard lab. Additionally, the core will use its biochemical expertise to quantify the existence of tau seeds for the other parts of the Center via RTQuiC assays. Together, the contributions from this Core will be significant as they will reveal fundamental mechanisms dictating tau turnover and provide novel targets for potential therapeutic intervention.