# Project 1: Tau metabolism: molecular chaperones, targeting and proteolysis

> **NIH NIH U54** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $655,218

## Abstract

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).

## Key facts

- **NIH application ID:** 10692748
- **Project number:** 5U54NS123985-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Aimee Kao
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $655,218
- **Award type:** 5
- **Project period:** 2021-09-27 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10692748

## Citation

> US National Institutes of Health, RePORTER application 10692748, Project 1: Tau metabolism: molecular chaperones, targeting and proteolysis (5U54NS123985-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10692748. Licensed CC0.

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