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A Journal on Internal Medicine

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Panminerva Medica 2001 December;43(4):283-7

language: English

A Yin-Yang role for metals in prion disease

Wong B.-S., Brown D. R. *, Sy M.-S.

From the Institute of Pathology Case Western Reserve University School of Medicine Cleveland, Ohio, USA
*Department of Biochemistry, Cambridge University Cambridge, UK


Prion dis­eas­es are not ­only genet­ic or spo­rad­ic neu­ro­de­gen­er­a­tive dis­or­ders, but ­more impor­tant, ­they are trans­mis­sible dis­eas­es. The etio­log­ical ­agent in ­these unprec­e­dent­ed dis­eas­es is ­believed to be ­prion pro­tein (PrP), ­which under­goes ­post-trans­la­tion­al con­ver­sion ­from the pre­dom­i­nant α-hel­i­cal con­for­ma­tion ­known as PrPC, to a β-­sheet ­rich abnor­mal iso­form ­called scra­pie PrP (PrPSc). Accumulating evi­dence has ­shown PrPC to be a cop­per-bind­ing anti­ox­i­dant in ­vivo. The pre­vail­ing ­view ­that PrP ­binds cop­per weak­ly is ­based on in ­vitro obser­va­tions ­using pep­tides or ­short frag­ment of recom­bi­nant PrP. However, ­recent in ­vitro evi­dence indi­cates ­human PrP has sig­nif­i­cant­ly high­er affin­ity for cop­per, sim­i­lar to oth­er cop­per-bind­ing pro­teins and cop­per ­uptake experi­ments ­show ­that PrP ­expressed by ­cells has a Km in the nano­mo­lar ­range. Besides bind­ing cop­per with­in the octar­e­peats ­region ­along the N-ter­mi­nus, PrP can ­also ­binds cop­per at a sec­ond ­site fur­ther ­upstream. More impor­tant­ly, PrP ­also ­binds oth­er met­als ­such as ­zinc and man­ga­nese at ­these two ­sites ­albeit at a low­er affin­ity. This is impor­tant ­because ­there is evi­dence ­that ­native PrP in ­prion dis­eas­es ­binds not ­only cop­per, but ­also ­zinc. This abnor­mal met­al bind­ing prob­ably result­ed in the ­loss of its ­anti-oxi­da­tion func­tion, and togeth­er ­with impair­ment in the cel­lu­lar anti­ox­i­dant mech­a­nisms, con­trib­ut­ed to the ­increased oxi­da­tive ­stress, and pos­sibly trig­ger neu­ro­de­gen­er­a­tion.

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