Show simple item record

Investigating the mechanism of GABA neuron degeneration in a model of coenzyme Q deficiency

dc.creatorHacker, Mallory Louise
dc.description.abstractNeurodegenerative diseases are characterized by inappropriate death of distinct neuronal populations. Although symptoms vary, these diseases share pathogenic features such as age-dependent onset and progressive death of specific neuronal subtypes. Additionally, dysfunction of mitochondria (essential energy-providing organelles) is widely associated with neurodegenerative disorders. Mitochondria are also key regulators of cell death pathways, further underscoring the need to understand how this organelle contributes to disease pathogenesis. This dissertation characterizes a novel neurodegeneration pathway induced by Coenzyme Q (CoQ) deficiency in C. elegans. CoQ depletion results in an age-related loss in motor coordination and selective degeneration of GABA neurons. My work establishes C. elegans as a model to study CoQ deficiency in the adult nervous system. Age-related onset, selective neuronal vulnerability and mitochondrial dysfunction are features of neurodegenerative diseases that are also prominent in our model of CoQ deficiency. This study also describes aspects of human CoQ deficiency that are conserved in C. elegans. My work supports a model of CoQ transport between tissues. This experimental paradigm has translational implications that could provide a genetic system to study regulators of CoQ uptake. Additionally, I show that localization and function of human CoQ biosynthetic enzymes is conserved in C. elegans. Together, this work emphasizes the strength of using C. elegans as a genetic model to study mechanisms that control CoQ uptake and function. I further investigate the mechanism of GABA neurodegeneration and discover novel roles for canonical apoptotic regulators. In response to CoQ depletion, GABA neurons activate a death pathway that requires CED-4/Apaf-1 but is antagonized by CED-3/caspase. This finding indicates that these components of the core cell death machinery adopt alternative roles in a degeneration pathway arising from CoQ depletion. I also address the role of necrotic proteases in this neurodegeneration pathway. This work revealed that the CoQ depletion-induced death pathway is controlled by proteases with death-promoting or death-preventing functions. Lastly, ultrastructural analysis identified features of necrosis in CoQ-deficient neurons. Together my work provides a foundation for studying neuronal responses to mitochondrial dysfunction.
dc.subjectC. elegans
dc.subjectCoenzyme Q
dc.titleInvestigating the mechanism of GABA neuron degeneration in a model of coenzyme Q deficiency
dc.contributor.committeeMemberDavid M. Miller III, Ph.D.
dc.contributor.committeeMemberLaura A. Lee, Ph.D.
dc.contributor.committeeMemberJoshua T. Gamse, Ph.D.
dc.contributor.committeeMemberAaron B. Bowman, Ph.D.
dc.type.materialtext and Developmental Biology University
dc.contributor.committeeChairKathleen L. Gould, Ph.D.

Files in this item


This item appears in the following Collection(s)

Show simple item record