PROJECT SUMMARY: Project 1 Tau accumulates in primary neurodegenerative tauopathies such as frontotemporal dementia (FTD, also FTLD-tau) and secondary tauopathies such as Alzheimer’s Disease (AD). Mutations and variants in MAPT and other genetic loci promote this accumulation. By necessity, many groups focus on one aspect of the tau metabolic pathway, such as interactions with molecular chaperones or autophagic clearance, or a single mutation, such as P301L tau. These types of focused pursuits have generated many insights into tau biology but have not yet led to comprehensive understanding of tau metabolism, both normally and in disease. The \ goal of this center is to provide a comprehensive assessment of tau metabolism, inclusive of wild-type and mutant tau, as well as including effects of other genetic modifiers. Within the context of the proposed FTD Center without Walls, this project will address the more upstream aspects of tau metabolism and homeostasis: from tau interactions with molecular chaperones to achieving tau degradation. The long-term goal of this FTD Center without Walls (CWOW) is to fully understand the metabolism of tau and how it changes with disease mutations and variants. The overall objective of this project is to assess three nodes of tau metabolic regulation: 1) interactions with molecular chaperones and co-chaperones, 2) effects of post-translational modifica- tions (PTMs) on proteasomal and lysosomal targeting and 3) efficiency of tau proteolysis by individual lysosomal proteases. This project’s central hypothesis is that molecular chaperones, proteosomal and lysosomal targeting and lysosomal proteases are all potential nodes at which MAPT and other genetic mutations can contribute to the aberrant tau homeostasis found in neurodegenerative diseases. The rationale for this work is that through systematic study of how tau metabolism changes with gene variants and disease, one can better comprehend the molecular perturbations predisposing to tauopathy. Such understanding would provide a conceptual framework for understanding protein metabolism in the field of neurodegeneration and could lead to better strategies to improve tau clearance for treatment and/or prevention of FTLD-tau and AD. Aim 1: Generate a mechanistic understanding of the consequences of tau, molecular chaperone and co-chaperone interactions. Aim 2: Determine the functional effects of PTMs on tau targeting to the proteasome and autophagy/lysosome systems. Aim 3: Test the functional effects of tau pathway variants on lysosomal proteolysis of tau. Together with the other Project and Cores, this Project will assess upstream nodes in the tau metabolic pathway. It will contribute to functional phenotyping of gene variants and their effect on tau metabolism to aid in building the resources generated by the FTD CWOW, namely the Tau Metabolic Pathway Database (TMDB) and the Tau Polygenic Risk Score (TPRS).