Adenylosuccinate Lyase Plays a Role in Neuromuscular Coordination
Open Access
- Author:
- Peifer, Mia
- Area of Honors:
- Biochemistry and Molecular Biology
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Wendy Hanna-Rose, Thesis Supervisor
Timothy Charles Meredith, Thesis Honors Advisor - Keywords:
- C. elegans
Adenylosuccinate Lyase Deficiency
Purine Metabolism
Neuromuscular Coordination - Abstract:
- Adenylosuccinate Lyase (ADSL) Deficiency is an ultra-rare purine metabolic disorder that results in severe neurobehavioral and neuromuscular defects. My lab has established an adsl-1 deficient Caenorhabditis elegans (C. elegans) model with phenotypes of altered learning, loss of muscle mass and integrity, and locomotive defects. Locomotive defects include slowed mobility and a distinct lack of coordination revealed by the inability to regulate the size of the body bend angles during swimming movement. Among the locomotive defects associated with an adsl-1 deficiency, we are particularly interested in understanding the mechanisms that cause adsl-1 animals to lose the ability to regulate body bending. Our adsl-1 deficient model has been useful in studying the mechanisms that underlie learning and neuromuscular defects associated with ADSL Deficiency. Because patients with ADSL Deficiency suffer from severe neuromuscular defects, I am interested in understanding the neural mechanisms that control the muscle function necessary to regulate body bending during swimming movement. I hypothesized that the inability to regulate body bending exhibited by adsl-1 deficient animals could be a result of perturbations to neural regulation of muscle function. To test this hypothesis, I reasoned that it would be optimal to first explore how the existing phenotypes associated with the loss of adsl-1 function contribute to coordination. This approach allowed me to determine whether any other pleiotropic effects of an adsl-1 deficiency contribute to the animal’s inability to regulate body bending before investigating the nervous system of C. elegans, which is its most complex system. To determine if these pleiotropic phenotypes play a role in neuromuscular coordination, I genetically and pharmacologically manipulated normal and adsl-1 deficient C. elegans and investigated how perturbations to tyramine signaling, muscular structural defects, general unhealthiness, and an inability to maintain normal rates of locomotion influence coordination. I found that adsl-1 animals share phenotypes with animals that have perturbations to tyramine signaling. This evidence supports the hypothesis that tyramine production is reduced upon the loss of adsl-1 function. However, further analysis of adsl-1 deficient animals and tyramine deficient animals suggests that reduced tyramine production does not play a role in the locomotive phenotypes associated with the loss of adsl-1 function. Thus, I explored alternative hypotheses for what contributes to the locomotive phenotypes associated with the loss of adsl-1 function with particular emphasis on understanding the etiology of the adsl-1-related coordination phenotype. I hypothesized that muscle weakness, slowed development, or reduced energy metabolism associated with an adsl-1 deficiency is causative of the coordination phenotype. I found that while these characteristics alone resulted in slowed mobility, they were not sufficient to recreate the coordination phenotype. As slowed mobility did not cause a lack of coordination, I sought to determine if the inability to maintain normal rates of swimming locomotion could directly cause animals to lose the ability to coordinate body bending during swimming. I observed swimming movement of animals with hyperactive muscle contraction and found evidence that suggests an animal’s inability to maintain normal rates of swimming locomotion does not directly impact coordination. My research suggests that perturbations to tyrosine metabolism, muscle structural defects, general unhealthiness, or the inability to maintain normal rates of locomotion associated with an adsl-1 deficiency do not directly cause the lack of coordination adsl-1 animals bend angle distribution reveals. These findings suggest that neural function of adsl-1 could play a key role in maintaining coordination. If so, the coordination phenotype could be useful for studying the role of adsl-1 in the neuron by serving as a model of the complex neurological and neuromuscular symptoms of an ADSL Deficiency. Understanding the mechanisms of the coordination phenotype and the role of adsl-1 in the neuron could be useful in providing new potential targets for the development of novel therapeutics that can be used to treat the devastating neuromuscular symptoms associated with ADSL Deficiency.