INVESTIGATING THE INTERPLAY BETWEEN BILE ACIDS AND PROTEIN AGGREGATION IN PARKINSON'S DISEASE AND COLORECTAL CANCER

Abstract

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by motor and non-motor symptoms, primarily due to the misfolding and aggregation of α-synuclein (α-syn). Although the mechanisms are not fully understood, recent studies indicate gastrointestinal dysfunction and altered gut microbiota in PD patients, affecting bile acid regulation and suggesting increased blood-brain barrier permeability. In the first part of my thesis, I investigated the effects of lithocholic acid (LCA) and deoxycholic acid (DCA) on α-syn aggregation and toxicity. LCA significantly accelerates the formation of toxic, SDS-resistant oligomers and fibrils, while DCA has a milder impact. Together, they synergistically enhance α-syn aggregation, highlighting the crucial relationship between bile acids and α-syn in PD. Targeting bile acid pathways may help modulate aggregation and slow disease progression, emphasizing gut-brain communication's role in neurodegenerative disorders. Cancer is increasingly recognized as a disease associated with protein aggregation, particularly with p53 aggregates in cancer cells. Colorectal cancer (CRC), a highly aggressive malignancy and the second leading cause of cancer-related deaths, is driven by mutations in the tumor suppressor gene TP53, which is essential for cell cycle regulation and apoptosis. Environmental factors, particularly bile acid metabolism, also influence CRC progression. In the second part of my thesis, I explored the impact of secondary bile acids, especially DCA and LCA, on the aggregation and stability of the R273 mutant p53 in CRC. My results indicated that bile acids, particularly LCA, enhance p53 aggregation and contribute to chemoresistance, especially in the R273H mutant. This suggests that bile acids disrupt cellular balance, complicating doxorubicin treatment. Finally, detecting protein aggregates in neurodegenerative diseases poses challenges due to traditional method's limitations. Thus, I examined gold nanoclusters as innovative, label-free sensing agents. Their unique physicochemical and luminescent properties offer exceptional selectivity and sensitivity, enabling effective differentiation between monomeric and aggregated forms of α-syn, paving the way for novel diagnostic applications.