Journal club. A systems biologist ponders how disparate ideas can sometimes come together beautifully.

TLDR: PrP can sequester cellular iron in insoluble PrP– ferritin complexes, making it biounavailable, leading to increased iron uptake and an overall excess of iron in brain tissue, and recognition of this could have a colossal effect on thinking and provide new therapeutic options based on iron chelation for these and other syndromes.

Abstract: If X alone and Y alone cannot explain a phenomenon, sometimes together they can. As the late biochemist Henrik Kacser remarked: “To understand the whole you must look at the whole.” Prion diseases, for example, are closely associated with the conformational change of the prion protein PrP from its normal form to an aggregating, autocatalysing, pathologic form, PrP. But clumping prions don’t tell the whole story. Their levels often correlate poorly with disease progression, and it is far from clear how a simple conformational change leads to the holes in brain tissue seen in late-stage disease. It is also clear that poorly liganded iron is highly neurotoxic, mainly because it can spur the production of the highly reactive and toxic hydroxyl radical OH — heavily involved in the progression of many other degenerative diseases and ageing. Neena Singh at Case Western Reserve University in Cleveland, Ohio, and her colleagues have now tied these two disparate threads together. PrP , they found, can sequester cellular iron in insoluble PrP– ferritin complexes, making it biounavailable, leading to increased iron uptake and an overall excess of iron in brain tissue (A. Singh et al., PLoS Pathog. 5, e1000336; 2009). Modified iron metabolism is found in both scrapie and sporadic Creutzfeldt–Jakob disease, and such work stresses that it is not only the total amount of Fe(ii) and Fe(iii) that matters but their speciation. It is yet to be shown whether PrP–ferritin complexes catalyse OH production directly, but if they do, this could account for the massive damage observed. Recognition of this could have a colossal effect on our thinking and provide new therapeutic (and dietary) options based on iron chelation for these and other syndromes. INVERTEBRATE IMMUNITY