Iron In Diseased Brains
ironjustice
Article Date: 16 Mar 2009 - 6:00 PDT
Imbalance of iron homeostasis is a common feature of prion disease-
affected human, mouse, and hamster brains, according to a new study by
Dr. Neena Singh and colleagues at Case Western Reserve University
School of Medicine, alongside collaborators from Creighton University.
These findings, published March 13 in the open-access journal PLoS
Pathogens, provide new insight into the mechanism of neurotoxicity in
prion disorders, and novel avenues for the development of therapeutic
strategies.
Unlike other neurodegenerative conditions, prion disorders are
sporadic, inherited, and infectious, and affect both humans and
animals; common examples are mad cow disease in cattle, scrapie in
sheep, and Creutzfeldt-Jakob disease in humans. The causative agent is
a misfolded protein referred to as PrP-scrapie that replicates itself
by changing the conformation of neighboring copies of the same
protein, namely the prion protein. Aggregates of PrP-scrapie are
toxic to brain cells and cause a spongy-like appearance in diseased
brains.
Research from the Singh laboratory suggests that accumulation of PrP-
scrapie alters the metabolism of iron in diseased brains. The
imbalance of brain iron homeostasis worsens with disease progression,
and is not an outcome of end- stage disease. Since iron is highly
toxic when mismanaged, this condition is likely to contribute
significantly to prion-disease-associated neurotoxicity. The likely
cause of this condition is loss of normal function of the prion
protein in cellular iron metabolism demonstrated recently by Singh and
colleagues, combined with gain of toxic function by the redox-active
PrP-scrapie complex as shown in this report.
Singh and her team were surprised to find that prion disease-affected
brains are iron deficient despite a significant increase in their
overall iron content. The group concludes that ferritin, a major iron
storage protein, co- aggregates with PrP-scrapie in diseased brains
and sequesters bound iron in the complex, creating a state of apparent
iron deficiency. The brain cells respond to this condition by
increasing their level of iron uptake, thus creating a vicious cycle
of increased iron uptake in the presence of increased iron.
These observations contribute to our understanding of how the prion
agent causes neurotoxicity, and may enable the development of novel
therapeutic strategies targeted at restoring brain iron homeostasis in
prion disorders.
CITATION:
Abnormal Brain Iron Homeostasis in Human and Animal Prion Disorders.
Singh A, Isaac AO, Luo X, Mohan ML, Cohen ML, et al. (2009)
PLoS Pathog 5(3): e1000336. doi:10.1371/journal.ppat.1000336
Click here to view article online.
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Source
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