Calcium Dyshomeostasis In Neurodegeneration

Author

Nicholas Emanuel Karagas, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical SciencesFollow

Author ORCID Identifier

https://orcid.org/0000-0002-7196-8014

Date of Graduation

12-2020

Document Type

Dissertation (PhD)

Program Affiliation

Cell and Regulatory Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Kartik Venkatachalam

Committee Member

Edgar T. Walters

Committee Member

Andrey Tsvetkov

Committee Member

Qingchun Tong

Committee Member

Hamed Jafar-Nejad

Abstract

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 Drosophila models of neurodegeneration.

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 Drosophila 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.

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 Drosophila 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.

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.

Keywords

neurodegeneration, calcium signaling, endoplasmic reticulum calcium channels, lysosomes, excitability, neuronal bioenergetics, longevity, Drosophila neurobiology, neuromuscular junction