Our hypothesis is that proper tau metabolism requires the precise, coordinated action of molecular chaperones, co-chaperones, post-translational modifications (PTMs), and degradation machinery that each represent regulatory nodes.
Genetic mutations in tau and other pathway members can disrupt tau metabolism, leading to tau accumulation, secretion, and neurodegeneration. We will generate critically important information about tau homeostasis and a foundational basis from which to build and frame subsequent investigations into tau pathobiology and toxicity.
Potential Nodes of Tau Regulation
FIGURE LEGEND
Overview model of tau metabolism showing potential nodes of regulation.
Briefly, tau interacts with a series of molecular chaperones and co-chaperones, undergoes extensive and dynamic post-translational modifications (PTMs), productive or non-productive protein clearance, aggregation, degradation, and/or secretion.
Tau Papers & Datasets
Single cell RNA-sequencing data derived from MAPT carriers and controls
Genome Med, 2023 See Paper; See Dataset
Sirkis D, Warly Solsberg C, Yokoyama J
Whole genome sequencing data derived from patients with Alzheimer's disease and frontotemporal dementia
See Dataset
Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation
Frontiers in Neurology, 2021 See Paper
Alquezar C, Arya S, Kao AW
Forthcoming Resources
Tau Metabolism & Variant Database (TMVdb)
Insights to MAPT and other key tau-metabolism genes
TMVdb will integrate findings from our Cores and Projects to produce a web-based and interactive guide on tau and tau-related proteins that will serve as a curated resource for the field.
Tau Polygenic Risk Score (TPRS)
Stratifying genetic risk for tauopathy
TPRS will integrate findings from our Cores and Projects to produce functional annotation of risk gene variants and will generate a polygenic risk score focused around tau-based neurodegeneration.