The long-term objective of the proposed work is to understand how environmental and genetic factors interact to influence selective neuropathology. The work contained within this proposal focuses on the influence of manganese (Mn) exposure on the pathophysiology of Huntington's disease (HD). Mn over-exposure has been associated with changes in iron homeostasis and energy metabolism, and has been shown to promote the aggregation of intrinsically amyloidogenic proteins. Furthermore, a major site of Mn accumulation in the brain is the corpus striatum, which contains the neurons most vulnerable in HD. The chronic neurotoxic stress rendered by the mutant HD gene has been associated with alterations in iron homeostasis, deficits in cellular energy metabolism, and accumulation of the disease protein into amyloid-like inclusions. These similarities in the pathophysiology of HD and Mn neurotoxicity suggest a potential for Mn exposure to modulate HD neuropathology. Using pilot project resources provided by the National Institute of Environmental Health Sciences (NIEHS) Core Center in Molecular Toxicology at Vanderbilt University, the investigators tested the influence of increased Mn exposure on a striatal cell model of HD. These pilot experiments revealed a surprising and exciting result, that mutant HD striatal cells are resistant to Mn toxicity and pathophysiologically relevant exposures to Mn suppress mutant HD phenotypes. This proposal will utilize cellular and mouse models of disease to examine the molecular basis of this gene-environment neuroprotective interaction and evaluate the potential of Mn exposure to modulate HD pathogenesis. These studies are organized around three specific aims. In the first of these the investigators will define the contribution of specific HD protein domains and specific cellular mediators of Mn action to the Mn-HD gene-environment interaction by functional domain mapping and evaluating other metals with similar neurotoxic properties. In the second aim the investigators will determine if Mn ions alter the conformational or functional properties of the HD protein by biochemical and biophysical protein assays utilizing cellular and animal models of HD. Then, in the third aim the investigators will evaluate known pathological endpoints of Mn toxicity and HD neuropathology to elucidate the physiological processes that underlie the Mn-HD interaction in vivo.
These specific aims are aligned with the mission of the NIEHS in that they examine the impact of a specific environmental toxicant on the pathophysiological processes of human disease. Finally, by exploring a gene-environment interface that moderates the onset and progression of HD, this study seeks to reveal mechanistic detail for how convergent genetic and environmental factors can enhance or suppress disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES016931-03
Application #
7848359
Study Section
Special Emphasis Panel (ZES1-JAB-C (R2))
Program Officer
Lawler, Cindy P
Project Start
2008-08-15
Project End
2013-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
3
Fiscal Year
2010
Total Cost
$410,317
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Neurology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Bryan, Miles R; Bowman, Aaron B (2017) Manganese and the Insulin-IGF Signaling Network in Huntington's Disease and Other Neurodegenerative Disorders. Adv Neurobiol 18:113-142
Di Pardo, Alba; Amico, Enrico; Basit, Abdul et al. (2017) Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington's disease. Sci Rep 7:5280
Pfalzer, Anna C; Bowman, Aaron B (2017) Relationships Between Essential Manganese Biology and Manganese Toxicity in Neurological Disease. Curr Environ Health Rep 4:223-228
Hollmann, Emma K; Bailey, Amanda K; Potharazu, Archit V et al. (2017) Accelerated differentiation of human induced pluripotent stem cells to blood-brain barrier endothelial cells. Fluids Barriers CNS 14:9
Bryan, Miles R; Uhouse, Michael A; Nordham, Kristen D et al. (2017) Phosphatidylinositol 3 kinase (PI3K) modulates manganese homeostasis and manganese-induced cell signaling in a murine striatal cell line. Neurotoxicology :
Bichell, Terry Jo V; Wegrzynowicz, Michal; Tipps, K Grace et al. (2017) Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington's disease mouse model. Biochim Biophys Acta 1863:1596-1604
Armstrong, Laura C; Westlake, Grant; Snow, John P et al. (2017) Heterozygous loss of TSC2 alters p53 signaling and human stem cell reprogramming. Hum Mol Genet 26:4629-4641
Brown, Jacquelyn A; Codreanu, Simona G; Shi, Mingjian et al. (2016) Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit. J Neuroinflammation 13:306
Osmand, Alexander P; Bichell, Terry Jo; Bowman, Aaron B et al. (2016) Embryonic Mutant Huntingtin Aggregate Formation in Mouse Models of Huntington's Disease. J Huntingtons Dis 5:343-346
Tidball, Andrew M; Neely, M Diana; Chamberlin, Reed et al. (2016) Genomic Instability Associated with p53 Knockdown in the Generation of Huntington's Disease Human Induced Pluripotent Stem Cells. PLoS One 11:e0150372

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