Role of metal dyshomeostasis and ubiquitin-proteasome system derangement in brain pathologies: risk factors and neuroprotective strategies

The ubiquitin-proteasome system (UPS) is the first line of defense in degrading soluble misfolded proteins. Maintaining
steady-state levels of proteasome composition and function is important for the maintenance of proteostasis in neuronal cells
which is vital for the physiology of neuronal cells. In addition and intertwined to proteostasis, a balanced metal ions
concentration and compartmentalization are required in order to maintain a correct functioning of the cell. Indeed, metal ions
dyshomeostasis as well as impairment of UPS have been associated with etiopathogenesis of neurodegenerative disorders,
such as Alzheimer Disease (AD), leading to the accumulation of toxic proteins and metal overloading in the neurons, which
both represent hallmarks for the development of neurodegenerative diseases. Moreover, defects and/or dysfunctions of the
UPS are also associated with the alteration of neuronal development and, therefore, they may underlie cognitive disorders,
such as Rett syndrome (RTT) and autism.
Based on these assumptions, here we propose a cross-disease analysis of apparently unrelated pathologies, AD and RTT. At
molecular level, we will mainly focus on the specific alterations of UPS functionality for the two diseases, taking into account
that any intervention on metal ions dyshomeostasis may also provide potential insight for the treatment of neuronal
disorders. The various units that will collaborate for this project have already reported that insulin-degrading-enzyme (IDE)
modulates proteasome activity in vitro and in cellular model. Moreover, they have recently shown that IDE is modulated by
metal ions and it is also able to activate ubiquitin (Ub), promoting the formation of K48 and K63 di-Ub. Here, we will
investigate the role of metal ions as well as the capability of IDE and Aβ to modulate proteasome activity through Ub
interaction and we expect to produce monoclonal antibodies against new disease markers found during the course of the
project. In addition, a main aim of this project is to identify and to validate novel molecules which could modulate UPS in
vitro and, among those, the most promising ones will be tested also in murine models of RTT and AD.
A traditional view on chronic neuropathological states focuses on individual, disease-specific enzymes and/or aggregating
proteins contributing to the different aspects of the neuropathologies. Nevertheless, cross-disease analysis of apparently
unrelated pathologies may represent a valuable approach to a detailed understanding of the underlying mechanisms
involved, thus providing a solid basis for the design of innovative therapeutic approaches. In this project, a multidisciplinary
analysis that combine various experimental approaches will be carried out for two apparently unrelated diseases, AD and
RTT.