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

Copyright © 2009 EDIZIONI MINERVA MEDICA

lingua: Inglese

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


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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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