# ATP13A2 and Susceptibility to Neurodegeneration

> **NIH NIH R01** · NORTHEAST OHIO MEDICAL UNIVERSITY · 2022 · $330,822

## Abstract

Project Summary/Abstract
Age-related neurodegenerative diseases are an increasing health and economic threat for millions of people
each year. Genetic susceptibility, environmental exposures, and age can all increase the risk of developing
neurodegenerative conditions such as synucleinopathies and manganism. The ATPase ATP13A2 is
associated with multiple age-related neurodegenerative conditions including Parkinson’s disease, the most
common synucleinopathy, Neuronal Ceroid Lipofuscinosis, and manganism and may be an important
protein linking key neurodegenerative disease risk factors. Identification of gene-environment interactions
associated with neurodegeneration is an important step to early detection, prevention, and treatment. The
objective of this proposal is to determine how ATP13A2 is involved in mitochondrial maintenance and how it
interacts with environmental and genetic risk factors to cause neurodegeneration. It is hypothesized that
loss of ATP13A2 function makes neurons more vulnerable to manganese and alpha-synuclein toxicity
through mechanisms involved in mitochondrial maintenance including repair and clearance mechanisms.
Further, this disruption may interact with aging and protein accumulation to produce enhanced
neurodegeneration and behavioural dysfunction. Our recent data shows that loss of function of ATP13A2 in
mice leads to an enhanced response to manganese and increased pathology in the brain. Guided by
preliminary data this hypothesis will be tested by pursuing three specific aims: 1) Determine the impact of
loss of ATP13A2 function on mitochondrial maintenance in vivo, 2) Assess the neurotoxic consequences of
Mn exposure in the presence of ATP13A2 loss on mitochondrial function in brain and periphery, and 3)
Identify the impact of loss of ATP13A2 function and increased alpha-synuclein burden on mitochondrial
maintenance and bioenergetics in vivo. Results from these studies are expected to have a positive impact
on our understanding of how gene-environment interactions can contribute to cellular dysfunction,
neurodegeneration, and behavioral impairments.

## Key facts

- **NIH application ID:** 10440477
- **Project number:** 5R01ES031124-03
- **Recipient organization:** NORTHEAST OHIO MEDICAL UNIVERSITY
- **Principal Investigator:** Sheila Fleming
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $330,822
- **Award type:** 5
- **Project period:** 2020-09-28 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440477

## Citation

> US National Institutes of Health, RePORTER application 10440477, ATP13A2 and Susceptibility to Neurodegeneration (5R01ES031124-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10440477. Licensed CC0.

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