REDOX METAL IONS AND NEURONAL PROTEIN DEPOSITION

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A common neuropathological feature of many neurodegenerative diseases, including Alzheimer s disease, Parkinson s disease, Huntington s disease, prion diseases and amyotrophic lateral sclerosis is the presence of focal markers of oxidative stress associated with proteinaceous deposits within the brain. In common with these diseases are a number of cuproproteins such as amyloid protein precursor (APP), prion protein, Huntingtin protein, monoamine oxidase and superoxide dismutase, which are implicated in the pathogenesis of these diseases. Recently, we have reported that APP and Abeta, the major component of amyloid, bind the redox metal ion copper with high affinity and that these proteins are capable of reducing Cu(II), with the subsequent generation of reactive oxygen species. Thus, the ability of Abeta to bind and reduce Cu(II) (and Fe(III) in the case of Abeta) engenders a situation whereby Abeta may be chemically modified, and may explain many of the others oxidative modifications observed in and around amyloid plaques. Indeed, we have shown that in the presence of redox active metals, Abeta forms sodium dodecyl sulphate-resistant polymers like those extracted from the AD brain. Thus, the recently reported uptake of metal ions by Abeta deposits may result in oxidative modifications that lead to the formation of Abeta polymers and the progressive deposition of Abeta into hard core amyloid plaques. It is possible that similar reactions also drive the deposition of other cuproproteins that deposit in neurodegenerative diseases. This study is designed to further characterize metal ion binding to proteins known to deposit within the brain, such as alpha- synuclein in Parkinson s disease, prion protein in prion diseases and Abeta in Alzheimer s disease. In addition, using standard analytical methods, we will test whether metal ions induce the aggregation and/or polymerization of alpha-synuclein and PrP. Finally, we will attempt to locate chemical modifications in these proteins that might explain the mechanism of polymerization. These data will be important in determining the mechanism behind neuronal protein precipitation and may yield insights into how to prevent their deposition in vivo.