From plant biodiversity to neuroprotection: identification and validation of natural bioactive compounds in models of Parkinson’s disease

This thesis is the result of the research work carried out at the University of Milano-Bicocca (Italy) under the supervision of Prof. Paola Coccetti. It also includes part of the results obtained during my external research activity at the Molecular Genetics of Development and Biomedical Models Laboratory, led by Prof. Nuria Paricio, in the Department of Genetics at the University of Valencia (Spain). This thesis addresses the investigation of innovative neuroprotective strategies, with particular focus on Parkinson’s disease (PD), a rapidly increasing neurodegenerative disorder (NDD) worldwide. The aggregation of α-synuclein (α-syn) protein is a central pathological hallmark of PD, and the identification of compounds able to prevent or attenuate α-syn aggregation represents a significant challenge in biomedical research. The main project of this thesis was conducted in close collaboration with researchers of the National Biodiversity Future Centre (NBFC) (Adopted by the Italian Ministry of University and Research, CUP, H43C22000530001, Spoke 6, Project title “National Biodiversity Future Center-NBFC”, https://www.nbfc.it/), which aims to valorize Italy’s rich plant biodiversity. Within this framework, a screening of 60 Italian plant species was performed to identify bioactive molecules with the capacity to inhibit α-syn aggregation and exert neuroprotective effects. Concurrently, within the scope of the “ON FOODS” project (Project code PE0000003 ON FOODS—CUP:H43C22000820001—Spoke 6, Project title “ON Foods—Research and innovation network on food and nutrition Sustainability, Safety and Security—Working ON Foods”), focused on the valorization of agro-industrial waste products, the neuroprotective potential of discarded by-products such as cocoa bean shells and leaves of Glycyrrhiza glabra were also evaluated. The efficacy of these compounds was assessed using multiple experimental models: Saccharomyces cerevisiae yeast cells and human SH-SY5Y neuroblastoma cells, both genetically engineered to overexpress α-syn, as well as a Drosophila melanogaster DJ-1β model of PD to investigate neuroprotective effects at the whole-organism level. The findings of this research are presented across three independent chapters, each containing a thorough introduction. The following sections will detail the individual studies, emphasizing the thematic and methodological continuity that underpins this multidisciplinary research effort.