The double faced role of copper in Ab homeostasis: A survey on the interrelationship between metal dyshomeostasis, UPS functioning and autophagy in neurodegeneration

Substantial evidence has accumulated over the last decade indicating that diverse age-related neurodegenerative disorders share a common pathogenic mechanism: the misfolding, aggregation and accumulation of proteins (termed “amyloid”) in neuronal tissues. The latest studies suggest that, in principle, any deficiency in protein homeostasis (proteostasis) may lead to cell dysfunction thus underscoring the protective key role played by systems regulating the clearance of misfolded or defective proteins in the cell. On the other hand, an altered metal homeostasis (metallostasis) is thought to be tightly linked to the malfunction of the “quality control” machinery of the cell. Metal ions have long been thought to catalyze amyloid aggregation by initiating protein misfolding. More specifically, redox active metal ions such as copper have been demonstrated to be majorly involved in a cascade of events resulting in oxidative damage and neurodegeneration. However, drugs aimed at merely removing excess of such metal ions from the cell have proven to be unsuccessful thus forcing scientists to amend these traditional views. In particular, a comprehensive vision of the interplay between metal dyshomeostasis and systems engaged in proteome maintenance, e.g. proteases, ubiquitin proteasome system (UPS) and autophagy, emerges as a critical requirement to single out the many culprits of cell dysfunction occurring in aging and in neurodegenerative pathologies such as Alzheimer's disease. Here, we will first provide a chemical perspective of the role of copper in Aβ homeostasis, thus giving the necessary outline to the problem of age-related protein misfolding and altered metallostasis which lead to accumulation processes and consequent decline of neuron functions. Secondly, we will focus on the proteome maintenance system (UPS and autophagy) and to the issues related to copper-mediated disturbances of the latter in AD. Finally, we will discuss the therapeutic potential of copper chelating agents in the treatment of neurodegenerative disorders