The complexity and multiplicity of factors involved in prion disease pathogenesis has hampered the search for an effective therapeutic strategy. Though each report has improved our understanding of prion disease pathogenesis, neither the normal function of prion protein (PrPC) nor the mechanism of toxicity by the disease associated conformer PrPSc is entirely clear. Reports of abnormal iron metabolism in prion infected neuroblastoma cells and mouse models implicate redox-iron mediated neurotoxicity in these disorders as has been proposed for several other neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and others. Recent data from my laboratory indicate that PrPC functions as an iron sensing, uptake, or transport protein in human neuroblastoma cells, and pathogenic mutations in PrPC alter cellular iron status in ways that are specific to each mutation. We have also noted evidence of abnormal iron metabolism in prion disease affected hamster and human brains, leading us to hypothesize that PrPC modulates cellular iron status by regulating iron uptake or transport, and alteration of this function due to point mutations or aggregation in the diseased state induces neurotoxicity. In the proposed studies we will check this hypothesis in two specific aims.
In aim 1 we will investigate whether PrPC is involved in cellular iron uptake, efflux, or transfer to ferritin, and identify PrP-interacting proteins or factors responsible for its iron modulating function.
In aim 2, the influence of pathogenic mutations of PrP on cellular iron status and susceptibility to free radical damage will be assessed. Cell lines exhibiting increased susceptibility to free radicals will be used to evaluate the protective effect of iron chelators and free radical scavenging compounds. These studies will improve understanding of prion disease pathogenesis in two distinct areas: 1) clarify the role of PrP in altering brain iron homeostasis during prion disease progression, and 2) validate the effectiveness of iron chelation in alleviating prion disease associated neurotoxicity.

Public Health Relevance

Prion diseases are fatal neurodegenerative disorders for which there is currently no treatment. These disorders are infectious, familial, and sporadic in nature. The principal infectious and pathogenic agent in all prion disorders comprises of a beta-sheet rich isoform of the prion protein termed PrP-scrapie (PrPSc). Our data suggest that imbalance in brain iron homeostasis helps in the generation and propagation of PrPSc and contributes to the neurodegeneration observed in these disorders. In the proposed studies we will test this hypothesis in cell models, and investigate whether iron chelation can be used as a therapeutic measure to alleviate prion disease associated neurotoxicity.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Mackiewicz, Miroslaw
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Case Western Reserve University
Schools of Medicine
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Singh, Ajay; Haldar, Swati; Horback, Katharine et al. (2013) Prion protein regulates iron transport by functioning as a ferrireductase. J Alzheimers Dis 35:541-52
Singh, Ajay; Qing, Liuting; Kong, Qingzhong et al. (2012) Change in the characteristics of ferritin induces iron imbalance in prion disease affected brains. Neurobiol Dis 45:930-8
Sunkesula, Solomon R B; Luo, Xiu; Das, Dola et al. (2010) Iron content of ferritin modulates its uptake by intestinal epithelium: implications for co-transport of prions. Mol Brain 3:14
Das, Dola; Luo, Xiu; Singh, Ajay et al. (2010) Paradoxical role of prion protein aggregates in redox-iron induced toxicity. PLoS One 5:e11420