Mathematical Modeling of Glucocerebrosidase Signalling Networks Linked to Neurodegeneration

In this paper, a computational model of signaling pathway networks related to glucocerebrosidase (GBA) mutation has been developed for a better understanding of its role in neurodegeneration. Changes in biochemical reactions due to GBA mutations have been reported as one of the causes of neurodegeneration in Alzheimer’s (AD) and Parkinson’s (PD) diseases. In this paper, the intracellular network has been reconstructed using biochemical systems theory and mathematical equations by applying kinetic laws. Protein concentrations and rate constants were extracted from literature for both normal and diseased conditions and from simulations; concentration changes were analyzed as a function of time. According to this model, the protein concentration levels of the GBA gene are decreased in both AD and PD conditions compared to control. This influenced autophagy lysosomal dysfunction, protein aggregation, oxidative stress, and neuroinflammation in both AD and PD networks. The model suggests that due to low GBA levels, cellular networks were also affected by the accumulation of abnormal proteins such as α-synuclein, β-amyloid, and GlcCer which can be considered as better biomarkers for the disease progression.