Normal prion protein regulates iron metabolism

March 13, 2013

An iron imbalance caused by prion proteins collecting in the brain is a likely cause of cell death in Creutzfeldt-Jakob disease (CJD), researchers at Case Western Reserve University School of Medicine have found.

The breakthrough follows discoveries that certain proteins found in the brains of Alzheimer's and Parkinson's patients also regulate . The results suggest that by the form of iron, called redox-active iron, may be a trait of neurodegenerative conditions in all three diseases, the researchers say.

Further, the role of the normal known as PrPc in iron metabolism may provide a target for strategies to maintain iron balance and reduce iron-induced neurotoxicity in patients suffering from CJD, a rare for which no cure yet exists.

The researchers report that lack of PrPC hampers iron uptake and storage and more findings are now in the online edition of the Journal of Alzheimer's Disease.

"There are many skeptics who think iron is a bystander or end-product of neuronal death and has no role to play in ," said Neena Singh, a professor of pathology and neurology at Case Western Reserve and the paper's senior author. "We're not saying that iron imbalance is the only cause, but failure to maintain stable levels of iron in the brain appears to contribute significantly to ."

Prions are misfolded forms of PrPC that are infectious and disease-causing agents of CJD. PrPc is the normal form present in all tissues including the brain. PrPc acts as a ferrireductase, that is, it helps to convert oxidized iron to a form that can be taken up and utilized by the cells, the scientists show.

In their investigation, mouse models that lacked PrPC were iron-deficient. By supplementing their diets with excess inorganic iron, normal levels of iron in the body were restored. When the supplements stopped, the mice returned to being iron-deficient.

Examination of iron metabolism pathways showed that the lack of PrPC impaired iron uptake and storage, and alternate mechanisms of iron uptake failed to compensate for the deficiency.

Cells have a tight regulatory system for iron uptake, storage and release. PrPC is an essential element in this process, and its aggregation in CJD possibly results in an environment of iron imbalance that is damaging to neuronal cells, Singh explained

It is likely that as CJD progresses and PrPC forms insoluble aggregates, loss of ferrireductase function combined with sequestration of iron in aggregates leads to insufficiency of iron in diseased brains, creating a potentially toxic environment, as reported earlier by this group and featured in Nature Journal club.

Recently, members of the Singh research team also helped to identify a highly accurate test to confirm the presence of CJD in living sufferers. They found that iron imbalance in the brain is reflected as a specific change in the levels of iron-management proteins other than PrPc in the cerebrospinal fluid. The fluid can be tapped to diagnose the disease with 88.9 percent accuracy, the researchers reported in the journal Antioxidants & Redox Signaling online last month.

Singh' s team is now investigating how prion protein functions to convert oxidized iron to a usable form. They are also evaluating the role of prion protein in brain , and whether the iron imbalance observed in cases of CJD, Alzheimer's disease and Parkinson's disease is reflected in the cerebrospinal fluid. A specific change in the fluid could provide a disease-specific diagnostic test for these disorders.

Explore further: International team discover clue to Friedreich's ataxia, devastating nervous system disease

Related Stories

International team discover clue to Friedreich's ataxia, devastating nervous system disease

November 23, 2012
(Medical Xpress)—A new form of iron may hold the clue that leads to treatment for a fatal inherited nervous system disease that can cause gait disturbance, speech problems, heart disease, diabetes and other symptoms. 

Recommended for you

Lifestyle changes to stave off Alzheimer's? Hints, no proof

July 20, 2017
There are no proven ways to stave off Alzheimer's, but a new report raises the prospect that avoiding nine key risks starting in childhood just might delay or even prevent about a third of dementia cases around the world.

Blood test identifies key Alzheimer's marker

July 19, 2017
A new study led by researchers at Washington University School of Medicine in St. Louis suggests that measures of amyloid beta in the blood have the potential to help identify people with altered levels of amyloid in their ...

Steering an enzyme's 'scissors' shows potential for stopping Alzheimer's disease

July 19, 2017
The old real estate adage about "location, location, location" might also apply to the biochemical genesis of Alzheimer's disease, according to new research from the University of British Columbia.

Brain scans may change care for some people with memory loss

July 19, 2017
Does it really take an expensive brain scan to diagnose Alzheimer's? Not everybody needs one but new research suggests that for a surprising number of patients whose memory problems are hard to pin down, PET scans may lead ...

Can poor sleep boost odds for Alzheimer's?

July 18, 2017
(HealthDay)— Breathing problems during sleep may signal an increased risk for Alzheimer's disease, a trio of studies suggests.

Hearing is believing: Speech may be a clue to mental decline

July 17, 2017
Your speech may, um, help reveal if you're uh ... developing thinking problems. More pauses, filler words and other verbal changes might be an early sign of mental decline, which can lead to Alzheimer's disease, a study suggests.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.