# Modulation of brain iron by local hepcidin in prion disorders

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $442,750

## Abstract

Prion disorders are infectious and invariably fatal neurodegenerative conditions associated with accumulation of
PrP-scrapie (PrPSc), a β-sheet rich isoform of the normal prion protein (PrPC), in the brain and retina of humans
and certain animal species. Sporadic Creutzfeldt-Jakob-disease (sCJD) is the most common human prion
disorder, and PrPSc-infected animal models are used to understand the mechanism of infectivity and toxicity.
Neuroinflammation and iron accumulation are consistent features of these disorders, the latter contributing to
neurotoxicity by iron-catalyzed reactive oxygen species (ROS). The cause of iron accumulation, however, has
remained elusive. Recent data from my laboratory suggest cytokine-mediated upregulation of hepcidin
synthesized by astrocytes as a significant cause. Hepcidin regulates iron by downregulating ferroportin (Fpn),
the only known iron export protein. Under normal conditions, hepcidin is upregulated when iron saturation of
transferrin (Tf-Fe) is low. Upregulation by cytokines, however, supersedes the signal from Tf-Fe. It is likely that
cytokine-mediated upregulation of hepcidin by astrocytes is the cause of iron neuronal accumulation that express
Fpn on their plasma membrane, and toxicity by ROS. In support of this hypothesis, sCJD brain homogenates
show upregulation of hepcidin mRNA and protein, downregulation of Fpn, and increase in ferritin. Likewise, brain
homogenates from PrPSc-infected mice show upregulation of hepcidin mRNA, and retinal sections from PrPSc-
infected hamsters show activation of microglia before or concomitant with upregulation of ferritin during disease
progression. Based on these observations, we hypothesize that iron accumulation in sCJD and PrPSc-infected
brains and retina results from cytokine-mediated upregulation of local hepcidin. Two specific aims are proposed
to test this hypothesis. In aim 1, additional sCJD brain and retinal tissue will be checked for increase in hepcidin
mRNA and accumulation of iron, and correlated with neuronal and retinal ganglion cell (RGC) death in
immunostained sections. In addition, the brain and retina of PrPSc-infected mice will be examined during disease
progression to explore if increase in cytokines precedes upregulation of hepcidin and iron accumulation, and
whether retinal degeneration precedes neurodegeneration. This will pave the way for retinal imaging a pre-
clinical diagnostic test for sCJD. In aim 2, the role of hepcidin in brain and retinal iron accumulation will be further
explored using hepcidin knock-out (hepc-/-) and littermate (hepc+/+) control mice inoculated with PrPSc. A
significant decrease in iron accumulation in hepc-/- mice relative to hepc+/+ controls despite similar increase in
cytokines and PrPSc load with disease progression will suggest local hepcidin as the cause of iron accumulation.
Moreover, a marked reduction in neuronal and RGC death in hepc-/- mice will suggest a significant role of iron in
inducing neurotoxicit...

## Key facts

- **NIH application ID:** 10350851
- **Project number:** 1R21NS125228-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Neena Singh
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $442,750
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10350851

## Citation

> US National Institutes of Health, RePORTER application 10350851, Modulation of brain iron by local hepcidin in prion disorders (1R21NS125228-01). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10350851. Licensed CC0.

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