Proteasomes modulation: implications in neurodegenerative diseases and cancer

Intracellular proteolysis is critical for controlling pathways such as cell cycle, cell growth and differentiation, apoptosis, regulation of transcriptional factors, carcinogenesis, removal of misfolded or damaged proteins, immune and inflammatory response. Consequently, alteration in protein degradation processes would inevitably lead to pathologic conditions. In fact, the accumulation of damaged proteins promotes the formation of toxic aggregates which alter normal cellular metabolism ultimately triggering apoptotic events. The main structure responsible for the degradation of most of the cytosolic and nuclear proteins in eukaryotic cells is the proteasome. This complex regulates several cellular pathways such as genes transcription, signal transduction, the immune response, carcinogenesis, cell division, DNA repair, morphogenesis of neuronal networks, biogenesis of organelles and apoptotic processes. Among proteasome substrates are included oxidized, damaged and misfolded proteins, the inhibitor of nuclear factor κB (NFκB; IκB), the tumor suppressor p53, the cyclin‐dependent kinase inhibitors p21 and p27 and the proapoptotic protein Bax. All these activities make the proteasomal complex an attractive field of research particularly for its implications in the onset of neurodegenerative diseases and cancer. In fact, Alzheimer's disease, Parkinson's disease and prion disorders present an altered proteasome functionality as a common hallmark that further contributes to the deposition of toxic protein aggregates. Furthermore, the modulation of proteasome activity is also considered a potential strategy to control cancer progression through the induction of apoptotic event in cancer cells. The aim of our studies is to further investigate the role of this complex in these disorders following two main lines of research.Initially, we have tried to better elucidate the interplay between the proteasome and those proteins involved in the onset of neurodegenerative diseases, such as amyloidbeta and prions. We have investigated the effects of different forms of amyloid aggregates on proteasome functionality both in isolated complexes and in neuronal cells obtaining a compromised activity, particularly in the presence of oligomeric structures. Then, analyzing brain regions of scrapie‐affected sheep compared to age matched healthy animals, we have measured proteasome activity and evaluated the intracellular localization of the complex and of the prion protein. Interestingly, we have observed an increased proteasome activity in affected animals and a coprecipitation and co‐localization of the two proteins, suggesting that prions affect substrate trafficking and modulate proteasome functionality. Regarding the modulation of proteasomal complexes in cancer, we have paid great attention to the effects of natural molecules, especially polyphenols, on its expression and catalytic activities and to the relation with the induction of apoptotic pathways. In detail, both in silico and in vitro studies have been used to gain insight into the proteasome/polyphenols interaction. We have characterized wheat sprout extracts for their polyphenolic content and then tested the effects on isolated and cellular proteasomes. Furthermore, we have separated two wheat sprout extract components, a polyphenol and a protein fraction and observed an in vitro inhibitory effect on proteasome activity from both components. Then, a comparative study of the effect of such components on both normal and tumor cells has been conducted and, interestingly, tumor cells have shown a significantly higher degree of proteasome impairment and apoptosis induction. Finally, considering their role in the carcinogenic process and in determining an enhancement in the cellular oxidative status, we have investigated if aflatoxins, a particular class of mycotoxins, and extremely low frequency electromagnetic fields may affect the proteasome, in order to evaluate if this complex takes part in their cellular harmful effects. On this regard, studies have been conducted both on isolated and cellular proteasomes. Globally, our results further demonstrate an involvement of the proteasome in numerous human pathologies, supporting the idea that it may play a strategic role as a therapeutic target for the treatment of such disorders.