# Tau Post-Translational Modifications and Mitochondrial Quality Control

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $583,420

## Abstract

Tau is a central player in the pathogenesis of numerous age-related neurodegenerative diseases,
with Alzheimer’s disease (AD) being the best example. Tau from AD brain is defined by aberrant
posttranslational modifications (PTMs), including increases in phosphorylation and acetylation at
specific epitopes. The UNDERLYING PREMISE of this proposal is that specific, disease relevant PTMs
impair tau function which negatively impacts neuronal health. While the formation of insoluble fibrillary
structures is influenced by PTMs, data strongly indicate that soluble forms of abnormally modified tau are
the mediators of neuronal toxicity. There are data indicating that overexpression of AD-relevant forms of
tau results in increased levels of fragmented, dysfunctional mitochondria, which may be due to in part
due to impaired mitophagy, as well as other perturbations of mitochondrial quality control (MQC)
mechanisms. However, a CRITICAL KNOWLEDGE GAP is how these modified tau species, when
present at physiologically relevant levels, influence mitochondrial and neuronal health. The OVERALL
HYPOTHESIS of this proposal is that tau with AD-relevant PTMs exerts toxic effects through impairing MQC
mechanisms. An impaired ability to resolve mitochondrial stress would increase the presence of less
functional mitochondria with a concomitant increase in oxidative stress and neuronal dysfunction. The
overall result would be an earlier onset of an aged neuron phenotype. The NOVELTY of this project stems
in part from its use of single-copy transgenic tau models that avoid overexpression, as well as the
inclusion of age as a variable in a genetic model organism. The nematode C. elegans benefits
from a vast repertoire of genetic, transgenic and genomic resources that will be leveraged to investigate the
molecular underpinnings of AD and to define the precise mechanism through which tau PTMs
compromise mitochondrial function and accelerate neuronal aging. Our preliminary data support this
approach as worms with single copy expression of tau with specific AD-relevant PTMs in
mechanosensory neurons show a significant increase in age-dependent neurodegeneration and a suppression
of stress-induced mitophagy. These and other preliminary data provide a strong foundation for the studies
in this application. The aims of this proposal are: (1) To determine the impact of AD relevant tau PTMs
on mitochondrial stress responses and how this influences healthy aging of neurons, (2) To test the
hypothesis that tau with AD relevant PTMs impairs mitochondrial dynamics and mitophagy, and (3) To
address whether enhancing MQC is a viable therapeutic avenue. The relative contribution of these responses
to neuronal age-dependent deficits will be tested using unique genetic resources available in worms. The
IMPACT of these studies will be to provide crucial new insights into the mechanisms by which
pathological tau species compromise mitochondrial function and neuronal health.

## Key facts

- **NIH application ID:** 9987176
- **Project number:** 1R01AG067617-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Gail V. W. Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $583,420
- **Award type:** 1
- **Project period:** 2020-06-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987176

## Citation

> US National Institutes of Health, RePORTER application 9987176, Tau Post-Translational Modifications and Mitochondrial Quality Control (1R01AG067617-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9987176. Licensed CC0.

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