Prion protein (PrPC) is a ubiquitously expressed cell surface glycoprotein known mostly for its role as the substrate for PrP-scrapie (PrPSc), the principal neurotoxic agent implicated in the pathogenesis of sporadic- Creutzfeldt-Jakob disease (sCJD) and other prion disorders. Consensus on the physiological function of PrPC or the mechanism of neurotoxicity by PrPSc, however, is lacking. Recent reports suggest that PrPC mediates cellular iron uptake by functioning as a ferrireductase (FR) partner for divalent metal transporters. Absence of PrPC in knockout mice (PrP-/-) induces iron deficiency in all systemic organs and the brain, indicating a non- redundant role in iron uptake, and the inability of other iron modulating proteins to compensate for its absence. It is therefore likely that the iron deficiency observed in sCJD and scrapie-infected animal brains that increases with disease progression and correlates with PrPSc is a result of loss of function of PrPC due to aggregation. The accompanying increase in total and redox-active iron in sCJD brains is perplexing, and is probably due to the sequestration of iron in a biological unavailable form in protease-resistant and detergent-insoluble ferritin aggregates. The associated changes in iron modulating proteins are reflected in the cerebrospinal fluid (CSF) in a disease-specific manner, providing a specificity of 92.5% in discriminating sCJD from other dementias. However, this specificity is likely to be obscured when neuroinflammation and associated microgliosis and astrocytosis supervene, causing active accumulation of iron in the neurons, microglia, and astrocytes. Based on these observations, we propose that loss or subversion of PrPC-mediated cellular iron uptake combined with sequestration of iron in PrPSc-ferritin complexes induces primary changes in brain iron metabolism that are modified by the secondary effects of neuroinflammation. Two broad aims are proposed to test this hypothesis.
In aim 1 we will investigate the significance of FR activity of PrPC in iron uptake by primary neurons and astrocytes, transformed cell lines, and relevant mouse models. PrPC- interacting divalent metal transporters will be identified, and disruption of cellular iron uptake by aggregation of PrPC in vitro and scrapie infection in vivo will be investigated.
In aim 2, mouse models of scrapie infection and inflammation will be used to identify changes in brain iron metabolism that are specific to scrapie infection, and those induced by concomitant or subsequent neuroinflammation and associated microgliosis and astrocytosis. The influence of PrPSc and super-imposed microgliosis and astrocytosis on the iron content and biochemical characteristics of ferritin will be investigated during disease progression to understand the cause of iron-rich, aggregated ferritin in sCJD brains. Successful completion of these studies will clarify the mechanism of brain iron dyshomeostasis in prion disorders, and will help in distinguishing sCJD-specific alterations in brain iron homeostasis form the secondary effects of neuroinflammation. This information is critical for the development of disease-specific therapeutic options that can arrest iron dyshomeostasis early in the disease course.
Our long term goal is to understand the mechanism of brain iron dyshomeostasis in sporadic Creutzfeldt-Jakob disease (sCJD). Emphasis will be placed on differentiating disease-specific triggers of brain iron dyshomeostasis from secondary events of gliosis and inflammation that are common to other neurodegenerative conditions. This distinction will help in the development of disease-specific therapeutic strategies to mitigate redox-iron induced neurotoxicity.
|Tripathi, Ajai K; Karmakar, Shilpita; Asthana, Abhishek et al. (2017) Transport of Non-Transferrin Bound Iron to the Brain: Implications for Alzheimer's Disease. J Alzheimers Dis 58:1109-1119|
|Baksi, Shounak; Singh, Neena (2017) ?-Synuclein impairs ferritinophagy in the retinal pigment epithelium: Implications for retinal iron dyshomeostasis in Parkinson's disease. Sci Rep 7:12843|
|Baksi, Shounak; Tripathi, Ajai K; Singh, Neena (2016) Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrin-bound iron: Implications for visual manifestations of Parkinson's disease. Free Radic Biol Med 97:292-306|
|Tripathi, Ajai K; Singh, Neena (2016) Prion Protein-Hemin Interaction Upregulates Hemoglobin Synthesis: Implications for Cerebral Hemorrhage and Sporadic Creutzfeldt-Jakob Disease. J Alzheimers Dis 51:107-21|
|Tripathi, Ajai K; Haldar, Swati; Qian, Juan et al. (2015) Prion protein functions as a ferrireductase partner for ZIP14 and DMT1. Free Radic Biol Med 84:322-330|
|Singh, Neena; Asthana, Abhishek; Baksi, Shounak et al. (2015) The prion-ZIP connection: From cousins to partners in iron uptake. Prion 9:420-8|
|Dev, Som; Kumari, Sanju; Singh, Neena et al. (2015) Role of extracellular Hydrogen peroxide in regulation of iron homeostasis genes in neuronal cells: Implication in iron accumulation. Free Radic Biol Med 86:78-89|