Coordination Chemistry Reviews 256 (2012) 2219–2224 Contents lists available at SciVerse ScienceDirect Coordination Chemistry Reviews jo ur n al homepage: www.elsevier.com/locate/ccr Review Coordination of zinc ions to the key proteins of neurodegenerative diseases: A, APP, -synuclein and PrP Vello Tõugu, Peep Palumaa ∗ Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia Contents 1. Introduction .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2219 2. Role of metal ions in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2220 2.1. Coordination of Zn(II) to APP .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2220 2.2. Coordination of Zn(II) to A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2221 3. Parkinson’s disease .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2222 3.1. Zn(II) and -synuclein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2222 4. Prion diseases .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2222 4.1. Prion protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2222 4.2. Coordination of Zn(II) to prion protein .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2223 5. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2223 Acknowledgements .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2223 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2223 a r t i c l e i n f o Article history: Received 31 October 2011 Accepted 16 December 2011 Available online 26 December 2011 Keywords: Zinc Alzheimer’s disease Parkinson disease Prion Amyloid- a b s t r a c t Major neurodegenerative disorders, including Alzheimer’s and Parkinsons’s disease and prion related pathologies are associated with protein misfolding and aggregation. Proteins involved in all the listed diseases are able to form complexes with metal ions and there is a dyshomeostasis and miscompart- mentalization of the transition metals in the brain during these diseases. Therefore, it is important to understand the interactions between the key proteins of the neurodegenerative diseases and the transi- tion metal ions and its consequences. We give a review on the coordination chemistry of zinc ions to A, APP, -synuclein and PrP. © 2011 Elsevier B.V. All rights reserved. 1. Introduction The major hallmark of neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s (PD) disease and transferable spongiform encephalitis (TSE) pathologies is the appearance of protein aggregates in the brain. The specific protein for each pathol- ogy misfolds in a fibrillar -sheet rich form and accumulates as insoluble deposits in the brain. Most of the amyloidogenic pro- teins involved in neurodegenerative diseases can interact with the Abbreviations: AD, Alzheimer’s disease; PD, Parkinson’s disease; TSE, transfer- able spongiform encephalitis; APP, amyloid- precursor protein; A, amyloid- peptide; PrP, prion protein; CuBD, copper binding domain. ∗ Corresponding author. Tel.: +372 620 4410; fax: +372 620 4401. E-mail address: peep.palumaa@ttu.ee (P. Palumaa). cations of transition metals–zinc, copper and iron whereas the binding of those ions leads to changes in the structure and func- tioning of the corresponding proteins. Two of these ions, Zn(II) and Cu(II), can be found in the brain of healthy persons in remarkable amounts in a loosely bound form, moreover, the age-dependent changes in the brain metal homeostasis further increases the avail- ability of copper and iron ions in the brains of the elderly. The above mentioned similarities, e.g. the formation of misfolded pro- tein aggregates and involvement of metal ions in this process have led to a hypothesis that the mechanisms of the neurodegenerative diseases are similar on the molecular level and that they are also connected to metal dyshomeostasis in the brain [1–3]. In this review we focus on the coordination of zinc ions to the key peptides and proteins of AD (amyloid precursor protein – APP, amyloid- –A), PD (-synuclein) and TSE (prion protein). APP has a copper binding domain, which can also bind Zn(II) ions. Other 0010-8545/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ccr.2011.12.008