The prion-ZIP connection: From cousins to partners in iron uptake

Singh, Neena; Asthana, Abhishek; Baksi, Shounak; Desai, Vilok; Haldar, Swati; Hari, Sahi; Tripathi, Ajai K.

doi:10.1080/19336896.2015.1118602

Cited by 12 publications

(7 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other than copper and manganese ions, zinc and iron ions are also essential metal ions in humans. In terms of iron, PrP C are considered to modulate iron homeostasis with the Zrt, Irt-like protein (ZIP) family [ 39 ], but the role of iron in the inflammation associated with prion disease is ambiguous. In regards to zinc, there are many studies focusing on zinc as an antagonist with copper [ 40 ], and PrP C can induce the uptake of zinc in neurons [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

The Effects of Divalent Cation-Chelated Prion Fibrils on the Immune Response of EOC 13.31 Microglia Cells

Jen

Lin

Guo

et al. 2020

Cells

View full text Add to dashboard Cite

Transmissible spongiform encephalopathies (TSEs) are epidemic neurodegenerative diseases caused by prion proteins; in particular, they are induced by misfolded prion proteins (PrPSc). PrPSc tend to aggregate into insoluble amyloid prion fibrils (fPrPWT), resulting in apoptosis of neuron cells and sequential neurodegeneration. Previous studies indicate that microglia cells play an important role in the innate immune system, and that these cells have good neuroprotection and delay the onset of TSEs. However, microglia can be a double-sided blade. For example, both Cu2+ and Mn2+ can induce microglia activation and secrete many inflammatory cytokines that are fatal to neuron cells. Unfortunately, PrP have cation binding sites at the N-terminus. When PrPSc accumulate during microglial phagocytosis, microglia may change the phenotype to secrete pro-inflammation cytokines, which increases the severity of the disease. Some studies have revealed an increase in the concentration of Mn2+ in the brains of patients. In this study, we treated microglia with fPrPWT and cations and determined IκBα and IL-1β expression by Western blotting and quantitative polymerase chain reaction. The results showed that Mn–fPrPWT decreased IκBα levels and dramatically increased IL-1β mRNA expression. In addition, competing binding between Cu2+ and Mn2+ can decrease the effect of Mn–fPrPWT on IκBα and IL-1β. The effects of divalent cations and fPrPWT in microglia inflammation are also discussed.

show abstract

Section: Discussionmentioning

confidence: 99%

The Effects of Divalent Cation-Chelated Prion Fibrils on the Immune Response of EOC 13.31 Microglia Cells

Jen

Lin

Guo

et al. 2020

Cells

View full text Add to dashboard Cite

show abstract

“…Interestingly, recent studies have shown that the prion protein (PrP), mutations of which causes prion disease, is also involved in transporting NTBI, at least in the liver, kidney, and neuroblastoma cells, by acting as a ferrireductase partner for ZIP14 and DMT1. 70–73 As discussed later in this review, α-synuclein, mutations of which cause Parkinson’s disease, also possesses ferrireductase activity and promotes Fe 2+ influx. 74–77…”

Section: Brain Iron Transportmentioning

confidence: 97%

Overdosing on iron: Elevated iron and degenerative brain disorders

D’Mello¹,

Kindy

2020

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

All cells in organisms ranging from yeast to humans utilize iron as a cofactor or structural element of proteins that function in diverse and critical cellular functions. However, deregulation of the homeostatic mechanisms regulating iron metabolism resulting in a reduction or excess of iron within the cell or outside of it can have serious effects to the health of cells and the organism. This review provides a brief overview of the molecular and cellular mechanisms regulating iron physiology, including the molecules and processes regulating iron uptake, its storage and utilization, its recycling, and its release from the cell, such that the cellular iron levels are sufficient to meet metabolic demand but below those that cause permanent damage. The major focus of review is on the pathological consequences of dysregulation of these homeostatic mechanisms, focusing on the brain. Current advances on the role of iron accumulation to the pathogenesis of rare neurological disorders caused by genetic mutations as well as to the more prevalent and age-associated neurodegenerative diseases are described. Impact statement Brain degenerative disorders, which include some neurodevelopmental disorders and age-associated diseases, cause debilitating neurological deficits and are generally fatal. A large body of emerging evidence indicates that iron accumulation in neurons within specific regions of the brain plays an important role in the pathogenesis of many of these disorders. Iron homeostasis is a highly complex and incompletely understood process involving a large number of regulatory molecules. Our review provides a description of what is known about how iron is obtained by the body and brain and how defects in the homeostatic processes could contribute to the development of brain diseases, focusing on Alzheimer’s disease and Parkinson’s disease as well as four other disorders belonging to a class of inherited conditions referred to as neurodegeneration based on iron accumulation (NBIA) disorders. A description of potential therapeutic approaches being tested for each of these different disorders is provided.

show abstract

“…A ferrireductase-deficient mutant of PrP (PrPΔ51–89) lacked this activity [ 66 ], suggesting that PrP C promotes the retrieval of iron via its ferrireductase activity. Additional research unveiled the mechanism of such PrP C modulation of kidney iron metabolism: a cellular prion protein acts as a ferrireductase partner and regulator for divalent metal iron transporters ZIP14 and DMT1 [ 109 , 110 ].…”

Section: Physiological Functions Of Prp C In the Kidneysmentioning

confidence: 99%

Harnessing the Physiological Functions of Cellular Prion Protein in the Kidneys: Applications for Treating Renal Diseases

Yoon¹,

Yoon

et al. 2021

Biomolecules

View full text Add to dashboard Cite

A cellular prion protein (PrPC) is a ubiquitous cell surface glycoprotein, and its physiological functions have been receiving increased attention. Endogenous PrPC is present in various kidney tissues and undergoes glomerular filtration. In prion diseases, abnormal prion proteins are found to accumulate in renal tissues and filtered into urine. Urinary prion protein could serve as a diagnostic biomarker. PrPC plays a role in cellular signaling pathways, reno-protective effects, and kidney iron uptake. PrPC signaling affects mitochondrial function via the ERK pathway and is affected by the regulatory influence of microRNAs, small molecules, and signaling proteins. Targeting PrPC in acute and chronic kidney disease could help improve iron homeostasis, ameliorate damage from ischemia/reperfusion injury, and enhance the efficacy of mesenchymal stem/stromal cell or extracellular vesicle-based therapeutic strategies. PrPC may also be under the influence of BMP/Smad signaling and affect the progression of TGF-β-related renal fibrosis. PrPC conveys TNF-α resistance in some renal cancers, and therefore, the coadministration of anti-PrPC antibodies improves chemotherapy. PrPC can be used to design antibody–drug conjugates, aptamer–drug conjugates, and customized tissue inhibitors of metalloproteinases to suppress cancer. With preclinical studies demonstrating promising results, further research on PrPC in the kidney may lead to innovative PrPC-based therapeutic strategies for renal disease.

show abstract

The prion-ZIP connection: From cousins to partners in iron uptake

Cited by 12 publications

References 35 publications

The Effects of Divalent Cation-Chelated Prion Fibrils on the Immune Response of EOC 13.31 Microglia Cells

The Effects of Divalent Cation-Chelated Prion Fibrils on the Immune Response of EOC 13.31 Microglia Cells

Overdosing on iron: Elevated iron and degenerative brain disorders

Harnessing the Physiological Functions of Cellular Prion Protein in the Kidneys: Applications for Treating Renal Diseases

Contact Info

Product

Resources

About