Introduction: Copper and amyloid fibril formation


Νeurodegenerative disorders such as Parkinson's disease and Alzheimer's disease (AD) are an increasing concern as the human population continues to age. As well as the social and economic burden that these diseases represent, they also are of considerable interest to researchers of protein chemistry. Several neurodegenerative disorders have a number of common features. These diseases all result in deposition of abnormal protein isoforms within the brain. The abnormal isoforms of these proteins can generate a variety of aggregate types. Chief among these are fibrils, often referred to as amyloid because of their association with amyloid plaques. Fibrils represent a form of ordered polymerization into long chains. Additionally, several of the proteins associated with these diseases have been found to bind copper. Amongst these proteins are the prion protein of prion diseases, both the amyloid precursor protein (APP) and amyloid-β (Aβ) of AD and, more recently, α-synculein of Parkinson's disease. In all cases, the normal isoform of the protein involved can bind copper but the functional consequences of this are still unclear.

Copper binding to potentially amyloidogenic proteins could have a variety of consequences. These are either to inhibit aggregation or promote it. Binding of copper to the normal prion protein can prevent its conversion to the disease specific isoform. However, once the disease process of prion disease has initiated protein conversion to the abnormal isoform, the presence of copper can stimulate this process. Copper can increase the infectivity of scrapie or increase the protease resistance of the prion protein. The use of copper chelators during disease progression has been shown to lengthen the disease process. These findings imply that the relationship between metals and amyloidogenesis is not a simple one. Interactions between proteins and copper need to be regulated. If this regulation breaks down, then there are consequences that could potentially trigger neurodegenerative disease.

Ιn the case of AD, the picture is further complicated in that copper binds both to the normal precursor and the disease specific protein. Copper binds to APP and prevents dimerization of the protein which is protective against cleavage of the protein by β-secretase, the enzyme complex known to cause the formation of Aβ. Once Aβ is formed, it can also bind copper. The presence of copper in preparations of Aβ is associated with its ability to aggregate. α-Synuclein is a protein associated with a number of diseases, including Parkinson's disease, and is the main component with Lewy bodies. Aggregation of α-synuclein can be triggered simply by high concentration of the protein. Binding of copper to this protein can increase its rate of aggregation.

In this issue of FEBS Journal, four minireviews are presented from major researches in the field of neurodegenerative diseases. Ilia Baskakov reviews his group's elegant work characterizing a model of prion fribril formation. He postulates that fibril formation in this model has unusual kinetics that are associated with branched chain fibrils. In another review, I present the current state of knowledge concerning the role of metals in Parkinson's disease with particular emphasis on copper binding to α-synuclein. Ashley Bush has been a chief advocate for the role of copper in AD and a review from his group (Crouch, White and Bush) discusses the potential for modulating metal bioavailability as a treatment for AD. Thomas Wisniewski has developed some ambitious new strategies for the treatment of both Alzheimer's and prion diseases and these are reviewed in the final review of the series. Together these, four reviews show the diversity of approaches used to study neurodegenerative diseases associated with amyloid fibril formation.

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[Professor David Brown was born in Sydney, Australia, but currently works in the Department of Biology and Biochemistry at the University of Bath in England. Professor Brown's main interest is the basic mechanisms behind neurodegenerative disorders. In particular, he has shown that metals bind to a variety of proteins, including the prion protein. His current work has focussed on metal binding to α-synculein. He serves as an editor for the Journal of Neurochemistry and is currently a member of the prestigious SEAC committee (Spongiform Encephalopathy Advisory Committee), advising the UK government on issues related to bovine spongiform encephalopathy and Creutzfeldt–Jakob disease.]