Exercise dramatically improves multiple facets of human health, but the molecular mechanisms by which exercise confers health benefits are not well understood. Known systemic benefits from exercise include substantial neuroprotection; for example, physical exercise is the sole intervention that improves patient outcomes and slows progression of Parkinson?s Disease. The mechanism for neuronal improvement is unclear, but an intriguing possibility is that protection is mediated through modulation of secreted proteins called neurotrophic factors. For example, recent studies have reported increased mesencephalic astrocyte- derived neurotrophic factor (MANF) levels after exercise. MANF is normally stored in the endoplasmic reticulum (ER), and is released upon conditions of ER stress. MANF specifically protects dopaminergic neurons, but the mechanisms by which MANF is protective, and the specific role of exercise in this process, are not well understood. Interestingly, MANF interacts with mitochondrial proteins, and mitochondrial content and activity are increased by exercise, raising the possibility that MANF mediates exercise-induced mitochondrial robustness. Understanding cellular and organism-wide mechanisms operating to confer benefits from exercise is essential for informing exercise recommendations for neurodegenerative disease and risk assessment for neurotoxicants. This Pathway to Independence career development award will experimentally test the relationship between physical exercise, the neurotrophic factor MANF, and chemical toxicant-induced neurodegeneration in the versatile model organism Caenorhabditis elegans. This model is especially appropriate for this question because MANF is the only neurotrophic factor conserved in nematodes, and my preliminary data shows swimming exercise in C. elegans concomitantly improves mitochondrial health and increases MANF expression. I hypothesize that exercise conditioning decreases neurodegeneration by protecting from chemical exposure-induced ER stress and mitochondrial dysfunction, and that this protection is mediated through the neurotrophic factor MANF. To test this hypothesis, I will subject wild-type, MANF- deficient, and MANF-overexpressing nematodes to exercise conditioning and/or neurotoxicant (rotenone and 6-hydroxydopamine) exposures. I will then determine the impact of MANF status on toxicant response by assessing ER stress, mitochondrial dysfunction, and neurodegeneration in the three MANF genetic backgrounds via the following aims:
Aim 1. Assess role of MANF in exercise-induced physiological changes;
Aim 2. Identify role of MANF in systemic crosstalk between ER stress and mitochondrial dysfunction after toxicant exposure;
Aim 3. Determine impact of exercise and MANF on toxicant-induced neurodegeneration. Overall, knowledge gained from this study will establish a model for long-term mechanistic dissection of exercise benefits in the context of both toxicant exposure and diseases of aging.

Public Health Relevance

Physical exercise is the sole intervention that improves patient outcomes and slows progression of Parkinson?s Disease, but the cellular mechanisms underlying those improvements are not well understood. Knowledge of the mechanisms by which exercise is neuroprotective will improve human health by giving new targets for therapeutic intervention and informing risk assessment for environmental exposures. This proposed research will examine the role of the neurotrophic factor MANF (mesencephalic astrocyte-derived neurotrophic factor) in mediating exercise protections from chemical exposure-induced mitochondrial dysfunction, endoplasmic reticulum stress, and neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Career Transition Award (K99)
Project #
1K99ES029552-01A1
Application #
9821602
Study Section
Special Emphasis Panel (ZES1)
Program Officer
Hollander, Jonathan
Project Start
2019-09-19
Project End
2021-08-31
Budget Start
2019-09-19
Budget End
2020-08-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Duke University
Department
Social Sciences
Type
Earth Sciences/Resources
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705