Metal based neurodegenerative diseases - From molecular mechanisms to therapeutic strategies

The hypothesis is presented that changes in metal ion homeostatic control, particularly of redox-active metals such as iron and copper, in specific brain regions, leads to the generation of reactive oxygen species, which either directly damage key proteins, or lead to the formation of reactive aldehydes. These, in turn, generate protein carbonyls, leading to protein denaturation, aggregation, and a failure of the ubiquitin/proteasome system to eliminate these defective proteins. We present the evidence for metal based neurodegeneration in Parkinson's and Alzheimer's disease. Possible therapeutic strategies are presented which could remove such excesses of these specific metals and lead to the diminishment of the neurodegenerative processes. (C) 2007 Elsevier B.V. All rights reserved