A Mathematical Model of Late Phase Calcium Dyshomeostasis in Axon Degeneration Promoted by SARM1's NAD Cleavage Activity
Date Thesis Awarded
Honors Thesis -- Access Restricted On-Campus Only
Bachelors of Science (BS)
Axon (Wallerian) degeneration, an early event preceding neuronal loss in neurodegenerative disease and traumatic brain injury, is the active process of dismantling the axon. Degeneration of the cytoskeleton occurs through the protease activity of calpains, which are activated by a characteristic late rise in intra-axonal calcium following axonal injury (execution phase). The increase in calcium may be influenced by the signature disruption of energy homeostasis in Wallerian degeneration; however, defining this relationship and the progression of the execution phase remains to be established. Recently, studies demonstrated that the executioner protein SARM1 performs NADase activity resulting in the generation of cyclic ADP-ribose. This novel SARM1 enzymatic activity may bridge the gap in understanding the relationship between these two events. Here, we use a computational model to investigate the relationship between energy state and intra-axonal calcium influenced by the enzymatic activity of SARM1. We have defined a mechanistic model that incorporates the cleavage products and can predict the effects on the temporal release of calcium from intracellular stores and monitor ATP and NAD concentrations. Construction of the mathematical model is based on Biochemical Systems Theory (BST), which has been applied successfully in predicting outcomes of neurodegenerative diseases. MATLAB analyzes the biochemical reactions represented as ordinary differential equations (ODEs) and allows for perturbations of the system to mimic experimental interventions. In our model, we have gathered data demonstrating a depleted energy state and altered calcium concentration from SARM1’s NADase activity promotes degeneration in axons. By comparing these data to results from axotomized primary neuronal cultures, we can assess the plausibility of the proposed mechanism occurring in vitro. The process of active degeneration in axons is complex and the use of a computational model representing the degeneration pathway will help elucidate its mechanisms and possibly provide insight for development of future therapeutic targets.
Crowley, Jessica, "A Mathematical Model of Late Phase Calcium Dyshomeostasis in Axon Degeneration Promoted by SARM1's NAD Cleavage Activity" (2018). Undergraduate Honors Theses. William & Mary. Paper 1172.
On-Campus Access Only