Environmental exposure to transition metals is linked to pathological processes of various neurodegenerative conditions since metal neurotoxicity often augments key degenerative changes including ionic imbalance, oxidative stress and protein aggregation. Several metal binding proteins regulate intracellular metal homeostasis and thereby maintain normal cellular function. Emerging evidence indicates that prion proteins are metal binding proteins that can efficiently bind to certain divalent cations including copper and manganese at the octapeptide repeat regions of the protein. Therefore, dysregulation of metal homeostasis has been suggested to play a role in the pathogenesis of prion diseases. Recent observations of elevated manganese (Mn) levels in the brain and blood of humans and animals afflicted with prion diseases suggest that manganese neurotoxicity may play a role in the etiology of prion diseases. Recently, we demonstrated that normal prion protein effectively attenuates manganese transport into neuronal cells and protects against manganese-induced oxidative stress, mitochondrial dysfunction, cellular antioxidant depletion, and apoptosis. While investigating these mechanisms, we unexpectedly found that manganese treatment upregulates cellular prion levels independent of transcription. Furthermore, we found manganese increases stability, suggesting that prion protein may promote the conversion of normal prion protein (PrPC) to the pathological form of prion (PrPSc), which results in the loss of normal prion protein's protective function against manganese neurotoxicity. Thus, the central hypothesis of this proposal is that manganese binds to the octapeptide (PHGGGWGQ) domain of cellular prion protein to increase the stability and accumulation of the protein. Manganese-induced stabilization of prion protein accelerates conformational conversion of PrPC to proteinase-resistant prion protein (PrPSc) aggregates and thereby induces neurotoxicity. This novel hypothesis will be tested through a systematic investigation of the following specific aims: i) to determine whether chronic exposure to manganese increases prion protein accumulation in animal models, ii) to determine the role of octapeptide repeat sequences in the manganese-induced stabilization of prion protein, iii) to determine whether chronic manganese exposure accelerates the accumulation and aggregation of the scrapie form of prion protein (PrPSc) and causes increased neuronal damage in a mouse model of prion disease, iv) to compare the effect of manganese on the accumulation and aggregation of PrPSc and on neuronal damage in mouse scrapie-infected prion overexpressing and octapeptide deletion transgenic animals (Tg20 and TgPrPDOR transgenic mice). Together, results from the proposed studies will not only provide new insights into the role of prion protein in manganese neurotoxicity but also will advance understanding of the role of metals in the pathogenesis of prion diseases.

Public Health Relevance

Manganese (Mn) is an essential trace elemental metal required by organisms for normal functioning;however, continued exposure to high concentrations of Mn results in adverse neurological deficits. The cellular prion protein is a putative metalloprotein since the octapeptide repeat sequences in the protein have high affinity for divalent cations including manganese, and the binding sites are suggested to play a role in the pathogenesis of prion diseases. Altered Mn content has been observed in the blood and brain of both human and animal prion diseases. Also, the role of prion protein in manganese neurotoxicity is currently unknown. Our proposal aims to determine the mechanisms of Mn interaction with prion protein in animal models to elucidate the pathophysiological mechanisms of prion diseases. The results of this study will not only provide new insights into the role of prion protein in manganese neurotoxicity but also will advance understanding of the role of metals in the pathogenesis of prion diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES019267-01
Application #
7949362
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Lawler, Cindy P
Project Start
2010-07-09
Project End
2015-06-30
Budget Start
2010-07-09
Budget End
2011-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$328,362
Indirect Cost
Name
Iowa State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
005309844
City
Ames
State
IA
Country
United States
Zip Code
50011
Harischandra, Dilshan S; Ghaisas, Shivani; Rokad, Dharmin et al. (2018) Environmental neurotoxicant manganese regulates exosome-mediated extracellular miRNAs in cell culture model of Parkinson's disease: Relevance to ?-synuclein misfolding in metal neurotoxicity. Neurotoxicology 64:267-277
Rokad, Dharmin; Ghaisas, Shivani; Harischandra, Dilshan S et al. (2017) Role of neurotoxicants and traumatic brain injury in ?-synuclein protein misfolding and aggregation. Brain Res Bull 133:60-70
Kim, Dong-Suk; Jin, Huajun; Anantharam, Vellareddy et al. (2017) p73 gene in dopaminergic neurons is highly susceptible to manganese neurotoxicity. Neurotoxicology 59:231-239
Harischandra, Dilshan S; Ghaisas, Shivani; Rokad, Dharmin et al. (2017) Exosomes in Toxicology: Relevance to Chemical Exposure and Pathogenesis of Environmentally Linked Diseases. Toxicol Sci 158:3-13
Manne, Sireesha; Kondru, Naveen; Nichols, Tracy et al. (2017) Ante-mortem detection of chronic wasting disease in recto-anal mucosa-associated lymphoid tissues from elk (Cervus elaphus nelsoni) using real-time quaking-induced conversion (RT-QuIC) assay: A blinded collaborative study. Prion 11:415-430
Kondru, Naveen; Manne, Sireesha; Greenlee, Justin et al. (2017) Integrated Organotypic Slice Cultures and RT-QuIC (OSCAR) Assay: Implications for Translational Discovery in Protein Misfolding Diseases. Sci Rep 7:43155
Yen, Chi-Fu; Harischandra, Dilshan S; Kanthasamy, Anumantha et al. (2016) Copper-induced structural conversion templates prion protein oligomerization and neurotoxicity. Sci Adv 2:e1600014
Ghaisas, Shivani; Maher, Joshua; Kanthasamy, Anumantha (2016) Gut microbiome in health and disease: Linking the microbiome-gut-brain axis and environmental factors in the pathogenesis of systemic and neurodegenerative diseases. Pharmacol Ther 158:52-62
Harischandra, Dilshan S; Jin, Huajun; Anantharam, Vellareddy et al. (2015) ?-Synuclein protects against manganese neurotoxic insult during the early stages of exposure in a dopaminergic cell model of Parkinson's disease. Toxicol Sci 143:454-68
Gendelman, Howard E; Anantharam, Vellareddy; Bronich, Tatiana et al. (2015) Nanoneuromedicines for degenerative, inflammatory, and infectious nervous system diseases. Nanomedicine 11:751-67

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