Analysis of functional and structural properties of different proteasome populations: implication in neurodegeneration

The dysregulation of the Ubiquitin proteasome system (UPS) is associated with neurodegeneration and, more generally, is considered as a hallmark of aging. The central element of UPS is the proteasome that is composed by the 20S core particle, to which alternative regulatory modules can associate to fine-tune its proteolytic activity. However, the molecular mechanism driving proteasome population interconversion and their substrate specificity are still largely unknown. A common feature of neurodegenerative diseases and aging is the accumulation of misfolded protein aggregates leading to a proteostasis derangement and to cell progressive death. In this project, a multidisciplinary analysis will be carried out to investigate both in vitro and in cellulo the enzymological properties of different proteasome populations (i.e. 20S, 20Si, 26S, PA28ab-20S, PA28g-20S) with particular emphasis to their ability to degrade denatured, misfolded, amyloidogenic and aggregation-prone proteins.