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Principal Investigator: Fleming, Sheila
Institute Receiving Award Northeast Ohio Medical University
Location Rootstown, OH
Grant Number R01ES031124
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 28 Sep 2020 to 30 Jun 2025
DESCRIPTION (provided by applicant): 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.
Science Code(s)/Area of Science(s) Primary: 63 - Neurodegenerative
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications No publications associated with this grant
Program Officer Jonathan Hollander
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