# Functional Characterization of Tau Mutation and Post-translational Modifications

> **NIH NIH K99** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $122,904

## Abstract

PROJECT SUMMARY/ ABSTRACT
 Protein aggregation is a hallmark of neurodegenerative diseases, including Alzheimer's Disease, and
these diseases lack effective therapeutics. We currently lack an understanding of the molecular and
cellular mechanisms controlling protein aggregation in the human brain, which would enable new
therapeutic strategies.
 The protein tau aggregates in the brain in a number of neurodegenerative diseases called tauopathies,
including Alzheimer's Disease. In early stages of disease, tau aggregates only in specific neurons despite
being expressed in every neuron in the brain, implying that specific factors in the cellular environment
predispose tau to aggregation. Similarly, tau mutations are associated with the onset of only specific
tauopathies. Together, these disease features imply that tau is exquisitely sensitive to both its sequence
properties and its cellular environment.
 Post-translational modifications (PTM) are a mechanism by which the cellular environment can act on a
protein similarly to mutation. Tau is heavily post-translationally modified and changes to tau PTMs are correlated
with progression of disease. Indeed, tau phosphorylation and proteolysis have been proposed to be central
events in the onset and progression of tauopathies. Similarly, mutations are correlated with early disease onset
and are known to hasten in vitro tau aggregation. Mutations can also cause changes in PTMs by changing tau
interaction partners. The function and causality of these changes to tau sequence, however, is unknown. I
hypothesize that PTMs and mutations license tau to access specific conformations to form aggregates.
 The goal of this proposal is to comprehensively identify (1) the biological basis of tau PTM
changes and (2) how tau mutation and PTMs cause aggregation. I have shown that mitochondrial electron
transport chain dysfunction causes a remodeling of tau PTMs, including the accumulation of a tau proteolytic
fragment. In Aim 1, I will acquire new training in mass spectrometry (MS)-based proteomics to determine the tau
PTM changes that occur due to ETC dysfunction and how those control tau aggregation. In Aim 2, I will use deep
mutational scanning (DMS) to comprehensively probe tau's sequence-structure relationship. As part of Aim 2, I
will use cross-link MS to directly compare in vitro and in vivo tau states to will reveal the structural mechanisms
for the identified PTM and sequence changes. I am ideally positioned to complete the proposed research, as
this proposal complements my training in protein biophysics and functional genomics in iPSC-derived neurons
with novel MS-based techniques. Completion of this proposal will identify which PTMs and mutations control
tau aggregation, as well as the development of new technologies to probe tau structure in vitro and in vivo.
Completion of this proposal will provide me with essential skills and training to be a successful independent
investigator.

## Key facts

- **NIH application ID:** 10828717
- **Project number:** 5K99AG080116-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Avi Jacob Samelson
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $122,904
- **Award type:** 5
- **Project period:** 2023-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828717

## Citation

> US National Institutes of Health, RePORTER application 10828717, Functional Characterization of Tau Mutation and Post-translational Modifications (5K99AG080116-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10828717. Licensed CC0.

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