Abstract/Summary

Neurodegenerative diseases have been identified and studied for decades but disease-modifying drugs are still unavailable for their majority. Their genetic and clinical complexity renders the identification of the precise molecular disease mechanism challenging. Holistic approaches that allow the analysis of diseases in a systems level, studying multiple genes and their protein products simultaneously, could aid in the endeavour to find treatment for neurodegenerative diseases, such as the Hereditary Spastic Paraplegias (HSPs) and Parkinson’s disease (PD). Firstly, a protein-protein interaction network (PPIN) analysis was performed centred on proteins derived from genes that lead to HSPs, revealing that their majority share at least one interactor. This suggests that they participate in common biological processes and pathways. Enrichment analysis highlighted membrane trafficking and vesicle mediated pathways as important for the HSPs. Furthermore, the clinical complexity of the disease led to the investigation of potential mechanistic differences of the disease depending on the mode of inheritance, type of HSP, and clinical features. The analysis of the latter also utilised basic machine learning tools (principal component analysis and hierarchical clustering) and suggested the existence of 2 subgroups of HSPs with divergent disease mechanisms. To investigate how a fundamental cellular process can contribute to disease, macroautophagy was studied, as it is associated with multiple neurodegenerative diseases. This connection was investigated initially by creating 5 PPINs (macroautophagy, PD, Alzheimer’s disease, Amyotrophic lateral sclerosis, and Frontotemporal dementia), and examining their overlap. As the intersection between all studied neurodegenerative diseases and macroautophagy was extensive, I focused on the relationship between macroautophagy and PD. This required the creation of a mathematical model of the initial stages of macroautophagy, in which differential protein amounts were used to simulate a healthy person versus a person with PD. Interestingly, this distinction in amounts was sufficient to simulate differential kinetics of macroautophagy.