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Keywords
PEPTIDES, METAL IONS, OXYDATIVE STRESS, UBIQUITIN-PROTEASOME SYSTEM, ANTIOXYDANT AND CHELATING COMPOUNDS, NEURODEGENERATION, STRUCTURE-ACTIVITY RELATIONSHIP

Role of metals – Ubiquitin/Proteasome interaction in the pathogenesis of conformational diseases

Università degli Studi di Catania
Abstract
It’s now recognised that several socially relevant neurodegenerative diseases, such as Alzheimer’s, Parkinson and Prion diseases, share the same pathogenic mechanism. Indeed, in each of these pathologies an abnormal increment of insoluble protein deposits, often referred to as “amyloids” can be found. Despite intense scientific effort has been addressed, during the last decades, to the comprehension of the molecular events underlying these pathologies, several unclear aspects have still to be unravelled before an effective therapy could be proposed. Yet, it has been demonstrated the determining role of several ageing-related factors, particularly the oxidative stress generated by ROS or the metals-promoted amyloidogenesis in consequence of perturbation, at a cellular level, of metal ions homeostasis.
Increasing experimental evidence suggests that in several pathologies linked to aberrant protein conformation, the normal protein turn-over inside the cell is inhibited. In Eukaryotes, physiological protein elimination inside the cell, is controlled by the Ubiquitin-Proteasome System (UPS), a complicated network of enzymatic reactions that, by using the ubiquitin as an identification tag for those protein destined to elimination and proteasome as the proteolytic machinery, degrades them into lower molecular weight fragments. Recent papers have demonstrated that divalent metal ions, (Cu2+, Fe2+ and Zn2+) including some red-ox active ones, can act as UPS inhibitors, thus >>>

Principal Investigator
Enrico Rizzarelli Università degli Studi di CATANIA
Research Objectives
The ubiquitin-proteasome system (UPS) has emerged as a predominant cellular regulatory machinery with roles in controlling cell-division, signal transduction, development and the immune response. It is also implicated in many neurodegenerative diseases, since cellular aggregates characterising neurodegeneration are heavily ubiquitinated. Despite the intense efforts aimed to elucidate the role played by UPS system in all these cellular processes, the mechanisms of protein regulation systems within the brain are poorly understood. Consequently, a long-term research goal is to understand protein regulation in the brain, and their implications in neurodegeneration and cell-cycle control. It is well known that the age-dependent rise in the brain of metal ions might contribute to hypermetallate many proteins, thus triggering misfolding and precipitation. However, the role played by metals in the disfunction of the ubiquitin-proteasome system is not completely understood. The present research project is aimed to investigate about the possibility that metal ions have to interact with the UPS and, as a consequence, to interfere with its normal activity. In this ligth, efforts will be mainly focused to elucidate the mechanisms by which components of the UPS may affect protein regulation and cell-cycle control within the brain. Dissection of the molecular mechanisms controlling protein turnover will not only enhance our understanding of these critical systems, but will also provide >>>

Timescale
24 months
National and international background
Several disorders, named "Conformational Diseases" [1], including the prevalent dementias and encephalopathies, are now believed to share the same general pathogenic mechanism. In each, there is an abnormal accumulation of insoluble aggregates that usually consist of fibrils containing a misfolded protein in a beta-sheet conformation, termed amyloid. The gradual accumulation of these aggregates and the acceleration of their formation by stressful environmental factors explain the characteristic late or episodic onset of the clinical symptoms. The understanding of these processes at the molecular level is opening prospects of more rational approaches to investigation and therapy [1]. There is partial but not perfect overlap among the cells in which misfolded proteins are deposited and the cells that degenerate. The most likely explanation is that inclusions and other visible protein aggregates represent an end stage of a molecular cascade of several steps, and that earlier steps in the cascade may be more directly tied to pathogenesis than the inclusions themselves [2]. There is no evident sequence or structural homology among the proteins that have been implicated in protein conformational disorders. However, there is accumulating evidence that the aggregates formed by the different misfolded proteins have the same molecular form.
Because of their insolubility and non-crystalline nature, high-resolution studies of aggregated proteins have been difficult. But >>>