# Role of mitochondrial GDAP1 in Alzheimer's disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $675,067

## Abstract

PROJECT SUMMARY
Despite extensive research, we still do not fully understand how neurons die in Alzheimer’s disease (AD) patients'
brains after withstanding decades of the accumulation of AD pathology. Oxidative damage and mitochondrial
deficits are proposed to contribute to or drive neurodegeneration in AD. AD brains show an accumulation of the
toxic end-product of lipid peroxidation 4-hydroxynoneal (4HNE), but it remains unclear what causes 4HNE to
accumulate in AD. Moreover, a mechanistic understanding of the increased sensitivity of mitochondria and
neurons in AD to oxidative damage is lacking. We determined that an atypical member of the glutathione S-
transferase (GST) superfamily, GDAP1 (Ganglioside Induced Differentiation Associated Protein 1), binds 4HNE
through a unique sequence motif called the α-loop, which is also essential for GDAP1 function. These data
collectively indicate that 4HNE is a GDAP1 substrate and that 4HNE binding to GDAP1 is essential for the
maintenance of cellular redox balance and mitochondrial function. Significantly, our preliminary RNAseq data
from AD patients and analysis of four AD proteomic datasets show significantly reduced levels of GDAP1 in the
prefrontal cortex of AD patients. As such, we hypothesize that GDAP1 protects mitochondria against oxidative
damage by neutralizing the highly toxic 4HNE and that reduced levels of GDAP1 render AD patient brains
vulnerable to 4HNE-mediated damage. We will test this hypothesis with two Aims. Aim 1 will determine the
mechanism of GDAP1-mediated cryoprotection including the mechanisms of 4HNE binding and detoxification.
Aim 2 will determine the impact of reduced levels of GDAP1 on mitochondrial function and accumulation of the
pathological hallmarks of AD in directly converted induced neurons from control subjects and AD patients. These
studies will establish the relationship between reduced GDAP1 levels, elevated 4HNE levels, and the increased
vulnerability of neurons in AD patients to oxidative damage and open a potential avenue for therapeutic
intervention in AD.

## Key facts

- **NIH application ID:** 10907007
- **Project number:** 5R01AG083877-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** KIRILL KISELYOV
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $675,067
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907007

## Citation

> US National Institutes of Health, RePORTER application 10907007, Role of mitochondrial GDAP1 in Alzheimer's disease (5R01AG083877-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10907007. Licensed CC0.

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