Upregulation of brain hepcidin in prion diseases

Abstract

Accumulation of redox-active iron in human sporadic Creutzfeldt-Jakob disease (sCJD) brain tissue and scrapie-infected mouse brains has been demonstrated previously. Here, we explored whether upregulation of local hepcidin secreted within the brain is the underlying cause of iron accumulation and associated toxicity. Using scrapie-infected mouse brains, we demonstrate transcriptional upregulation of hepcidin relative to controls. As a result, ferroportin (Fpn), the downstream effector of hepcidin and the only known iron export protein was downregulated, and ferritin, an iron storage protein was upregulated, suggesting increased intracellular iron. A similar transcriptional and translational upregulation of hepcidin, and decreased expression of Fpn and an increase in ferritin expression was observed in sCJD brain tissue. Further evaluation in human neuroblastoma cells (M17) exposed to synthetic mini-hepcidin showed downregulation of Fpn, upregulation of ferritin, and an increase in reactive oxygen species (ROS), resulting in cytotoxicity in a dose-dependent manner. Similar effects were noted in primary neurons isolated from mouse brain. As in M17 cells, primary neurons accumulated ferritin and ROS, and showed toxicity at five times lower concentration of mini-hepcidin. These observations suggest that upregulation of brain hepcidin plays a significant role in iron accumulation and associated neurotoxicity in human and animal prion disorders.

Minimal change prion retinopathy: Morphometric comparison of retinal and brain prion deposits in Creutzfeldt-Jakob disease

“…Altogether, these findings suggest that neurodegenerative sequelae observed in the inner retina structures (GCL and NFL) and the optic nerve during the course of sCJD, may be either a direct consequence of OPL PrP Sc deposition, an indirect consequence of other sCJD related ocular stressors (e.g. accumulation of redox-active iron), or a combination of such contributing factors ( Chaudhary et al, 2021 ).…”

Iron and Ferroptosis More than a Suspect: Beyond the Most Common Mechanisms of Neurodegeneration for New Therapeutic Approaches to Cognitive Decline and Dementia

“…Symptoms of CJD include dementia that quickly gets worse over a few weeks or months, muscle stiffness, twitching, weakness, and problems with coordination and balance. CJD has no cure, and treatment focuses on relieving symptoms [14]. Studies have shown that sCJD-affected human brains show an increase in total iron, and there is a direct correlation between prion protein (PrP) deposition and transferrin (Tf) levels, implicating PrPSc as the underlying cause of the iron deficiency.…”

“…Hepcidin, a key regulator of iron homeostasis, upregulated in the brain, has been demonstrated in prion diseases, including sCJD. This upregulation may contribute to iron dysregulation in prion disease-affected brains [14].…”

“…When iron homeostasis is disrupted, iron accumulation can generate free radicals, resulting in high toxicity [11] responsible for metabolic diseases, such as non-alcoholic steatohepatitis, atherosclerosis, stroke, and type 2 diabetes [12], as well as for neurodegenerative diseases, such as Parkinson's disease (PD) [13], multiple sclerosis (MS) [13], Alzheimer's disease (AD) [6], prion diseases such as Creutzfeldt-Jakob's disease (sCJD) [14], and amyotrophic lateral sclerosis (ALS) [13]. In addition, iron metabolism worsens in aging, causing iron accumulation, and affecting the inflammatory process, protein aggregation, and neuronal function [11].…”