# Ubiquitination of Mitochondrial Proteins in Alzheimer's Disease

> **NIH NIH R21** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2024 · $436,150

## Abstract

PROJECT SUMMARY/ABSTRACT
Extensive studies have observed impaired mitochondria in patients and animal models of Alzheimer’s disease
(AD). Specifically, a large body of research has made the connection between altered mitochondria functions
and accumulation of amyloid-β (Aβ) peptides in various experimental systems. However, given the complex
functions of mitochondria and Aβ, further research remains overwhelmingly needed to better understand
mitochondrial dysfunction in AD in order to reveal promising therapeutic targets. To approach this question, we
have collected a large amount of preliminary data to show that a E3 ubiquitin ligase, named neural precursor
cell-expressed developmentally down-regulated gene 4-like (Nedd4L), is associated with mitochondria and
regulates mitochondrial membrane potential. We further showed that Nedd4L is dephosphorylated in a familial
AD mouse model, APP/PS1 mice, and dephosphorylated Nedd4L ubiquitinates a mitochondrial outer membrane
protein mitofusion-2 (MFN2). Previous studies have observed downregulation of MFN2 in post-mortem patient
samples and animal models of AD and suggest a contribution of MFN2 downregulation in AD pathogenesis.
Based on these data and prior research, we hypothesize that dephosphorylation of Nedd4L in APP/PS1 mice
contributes to impaired mitochondrial function and neurodegeneration in part through ubiquitinating MFN2. We
will test this hypothesis with two aims. Aim 1 will employ multiple unique mouse models to determine how the
two major isoforms of Nedd4L differentially regulate mitochondrial functions and how dephosphorylation of
Nedd4L affects those functions. Aim 2 will employ a cell-permeable peptide to promote phosphorylation of
endogenous Nedd4L in vivo to assess the impacts of Nedd4L dephosphorylation on neuronal functions and
health in APP/PS1 mice. Our goals are to establish Nedd4L as an upstream regulator contributing to the
dysfunctions of MFN2 and mitochondria in APP/PS1 mice and to introduce approaches that can rectify or
ameliorate the impairment.

## Key facts

- **NIH application ID:** 10989375
- **Project number:** 1R21AG089491-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Nien-Pei Tsai
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $436,150
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10989375

## Citation

> US National Institutes of Health, RePORTER application 10989375, Ubiquitination of Mitochondrial Proteins in Alzheimer's Disease (1R21AG089491-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10989375. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*