Calcium Dyshomeostasis In Neurodegeneration

<p>Neurodegenerative diseases, despite constituting a major and growing cause of mortality globally, have few effective treatments. In order to develop novel therapeutics to combat neurodegeneration, a better understanding of the molecular mechanisms underlying these diseases is needed. Neurons rely on Ca²⁺ to mediate many of their unique functions, and aberrant Ca²⁺ signaling has been broadly implicated in neurodegeneration. The goal of this dissertation is to delineate specific examples of Ca²⁺ dyshomeostasis that I have uncovered in <em>Drosophila </em>models of neurodegeneration.</p> <p>I first define the role a neurodegeneration-associated mutation plays in perturbing presynaptic [Ca²⁺], which is an important determinant of proper morphological development of the <em>Drosophila </em>neuromuscular junction (NMJ). While previous reports have shown how low [Ca²⁺] contributes to morphological defects in synaptic boutons by destabilizing microtubules, this project elaborates on this story by demonstrating that high [Ca²⁺] can also cause a similar phenotype. Deviations in typical presynaptic [Ca²⁺] that result in improper NMJ morphology are mediated by a pair of counteracting Ca²⁺-sensitive enzymes, a phosphatase and a kinase, which act on the same microtubule-stabilizing substrate.</p> <p>I next describe how depolarization of the plasma membrane potentiates Phospholipase Cβ (PLCβ) activity, which led to greater inositol trisphosphate receptor (IP₃R)-mediated Ca²⁺ release. Depolarization-induced augmentation of PLCβ-IP₃R signaling increased mitochondrial [Ca²⁺] and ATP production, suggesting that activity of this mechanism constitutes a homeostatic response that compensates for the intensive bioenergetic needs of the neuron. Furthermore, in <em>Drosophila </em>models of neurodegeneration that decouple depolarization from this putative homeostatic response, misappropriation of this signaling axis induced increased endolysosomal Ca²⁺ loading, and a reduction in longevity. Interventions that decreased PLCβ-IP₃R signaling or attenuated endolysosomal Ca²⁺ overload prevented shortening of lifespan in flies expressing neurodegenerative transgenes.</p> <p>This dissertation endeavors to expand the body of knowledge describing mechanisms of Ca²⁺ dyshomeostasis that are relevant to neurodegeneration. I hope that, in the future, what is outlined here will contribute to the development of therapeutics needed to combat neurodegenerative diseases.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2020

Authors dc:creator

• Karagas, Nicholas Emanuel
• <p>https://orcid.org/0000-0002-7196-8014</p>

Contributors dc:contributor

• Kartik Venkatachalam
• Edgar T. Walters
• Andrey Tsvetkov

• neurodegeneration
• calcium signaling
• endoplasmic reticulum calcium channels
• lysosomes
• excitability
• neuronal bioenergetics
• longevity
• Drosophila neurobiology
• neuromuscular junction
• Cell Biology
• Molecular and Cellular Neuroscience
• Molecular Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1053

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2108