The double faced role of copper in Ab homeostasis: A survey on the interrelationship between metal dyshomeostasis, UPS functioning and autophagy in neurodegeneration
The double faced role of copper in Ab homeostasis: A survey on the interrelationship between metal dyshomeostasis, UPS functioning and autophagy in neurodegeneration(384 views) Grasso G, Santoro AM, Lanza V, Sbardella D, Tundo GR, Ciaccio C, Marini S, Coletta M, Milardi D
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 Ab 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
The double faced role of copper in Ab homeostasis: A survey on the interrelationship between metal dyshomeostasis, UPS functioning and autophagy in neurodegeneration
The double faced role of copper in Ab homeostasis: A survey on the interrelationship between metal dyshomeostasis, UPS functioning and autophagy in neurodegeneration