Systems biology of inherited metabolic diseases: A focus on Gaucher disease and connections to Parkinson’s disease

Inherited metabolic diseases are complex disorders in which molecular defects propagate across interconnected biological systems, producing phenotypes that cannot be fully understood through reductionist approaches alone. Systems biology helps address this challenge by integrating large-scale biological data with mathematical and computational methods to characterise and predict the behaviour of cells and tissues. Within this framework, metabolic modelling focuses specifically on the metabolic network, allowing investigation of pathway activity, reaction flux, and system-wide responses to perturbations such as gene mutations or altered nutrient conditions. This thesis applies constraint-based modelling to investigate inherited metabolic disease, with a particular focus on Gaucher disease and its relationship with Parkinson’s disease. Constraint-based modelling relies on network stoichiometry and physicochemical constraints, including mass balance, reaction directionality, and capacity limits, to define feasible metabolic states under the steady-state assumption. Two optimisation approaches are central to this work: flux balance analysis (FBA), which predicts metabolic fluxes by optimising a biological objective, and entropic flux balance analysis (entropicFBA), which favours more biologically plausible and flexible flux distributions. The thesis is further grounded in the use of genome-scale metabolic models, which provide a systems-level representation of cellular metabolism by linking genes, proteins, reactions, and metabolites. Among currently available human reconstructions, Recon3D was selected for its incorporation of three-dimensional protein structural information, enabling more mechanistic interpretation of genotype–phenotype relationships and disease-associated metabolic disruption. Context-specific models are used to capture active metabolic networks in distinct biological settings and thereby improve phenotype prediction. This thesis has three main aims. First, it seeks to consolidate current understanding of the pathological consequences of GBA1 mutations through critical review of the literature. Second, it reconstructs and analyses a genome-scale metabolic model of macrophages in Gaucher disease and control states to characterise the metabolic consequences of glucocerebrosidase deficiency. Third, it investigates the genetic and transcriptomic basis underlying the increased incidence of Parkinson’s disease among GBA variant carriers. Together, these aims provide an integrated framework for studying metabolic dysfunction in Gaucher disease and its mechanistic links to Parkinson’s disease.

Publisher

University of Galway

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CC BY-NC-ND

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University of Galway Theses (PhD Theses)