Thesis
Influences of CU/ZN Superoxide Dismutase Mutations on Drosophila Motor Neuron Morphology and Mitochondria
University of Iowa
Master of Science (MS), University of Iowa
Spring 2020
DOI: 10.17077/etd.005437
Abstract
Superoxide dismutases are well-known as major mechanisms employed by organisms throughout nature to combat oxidative stress. What are less well understood are the mechanisms by which mutations in the Cu/Zn superoxide dismutase (SOD1) are associated with motor neuron degeneration, as they appear to be in the disease amyotrophic lateral sclerosis (ALS). The human lethality of ALS-related SOD1 mutations is replicated in Drosophila melanogaster when mutations are introduced to the homologous Drosophila gene for SOD1 (Sod). The deleterious effects of Sod mutations can appear as early in the Drosophila lifecycle as the larval and pupal stages, especially when the organisms are reared under heat stress. Abnormal motor neuron physiology induced by Sod mutations manifests itself at the larval neuromuscular junction (NMJ), in the form of unusual synaptic bouton morphology, which, like the basic developmental lethality phenotype, is exacerbated by long-term heat stress. The mutant larval NMJs were also found to contain abnormal aggregates of mitochondria, which tended to reside inside synaptic boutons of enlarged, swollen morphology. Cultured giant motor neurons derived from lineage-identified, cytokinesis-arrested neuroblasts in Sod mutant embryos displayed atypical overgrowth, both in the number of neurites per cell, and in the complexity of neurite ramification. Like the larval NMJ, giant neurons mutant for Sod exhibited mitochondrial aggregation, but this only became prominent after the cells had been aged to a time point roughly equivalent to the age at which the third-instar larval NMJ was studied. The age at which mitochondrial aggregates became more frequent in cultured Sod motor neurons was also the time point at which neurites of many mutant neurons developed membrane swellings. Neurite swellings in wild-type are frequently followed by neurite degeneration. Together, these results demonstrate the presence of early morphological and mitochondrial phenotypes in Sod mutant motor neurons, both in vivo and in vitro, corresponding to known physiological alterations. The results from the culture system suggest cellular autonomy and age-dependence of the mitochondrial phenotype, which may hold true for other phenotypes linked to the same mechanisms. With this insight into what may be very early stages of neurodegeneration, we can better understand where and when to continue investigating processes leading up to irreversible motor neuron degeneration in SOD1-related ALS.
Details
- Title: Subtitle
- Influences of CU/ZN Superoxide Dismutase Mutations on Drosophila Motor Neuron Morphology and Mitochondria
- Creators
- Tristan C. D. G. O'Harrow
- Contributors
- Chun-Fang Wu (Advisor)Michael E. Dailey (Committee Member)Toshihiro Kitamoto (Committee Member)
- Resource Type
- Thesis
- Degree Awarded
- Master of Science (MS), University of Iowa
- Degree in
- Biology
- Date degree season
- Spring 2020
- Publisher
- University of Iowa
- DOI
- 10.17077/etd.005437
- Number of pages
- vi, 55 pages
- Copyright
- Copyright 2020 Tristan C. D. G. O'Harrow
- Comment
This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: https://www.lib.uiowa.edu/sc/contact/.
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 50-55).
- Public Abstract (ETD)
Oxidative stress is a type of physiological strain, generally considered an aspect of aging, put on the bodies of living creatures by metabolic processes. The Cu/Zn superoxide dismutase, also known as SOD1, is an enzyme produced by our bodies to keep oxidative stress under control. Mutations in the gene for SOD1 have been found in some patients of the fatal and incurable disease ALS, also known as Lou Gehrig’s or motor neuron disease. Somehow, SOD1 mutations are related to the slow death of motor neurons, leading to the weakening and wasting-away of muscles needed for voluntary movement, swallowing, and breathing. Fruit flies carrying SOD1 mutations also exhibit motor deficiencies and early death, making them a good model in which to look for the earliest stages of motor neuron degeneration. This study shows, through experiments on larvae and on motor neurons grown in a dish, that the some of the earliest stages of motor neuron illness involve abnormal clumping of mitochondria inside the neurons, accompanied by swellings in the neurons' branches. The next steps will involve finding out what mechanisms cause these effects, and how they later lead to animal death.
- Academic Unit
- Biology
- Record Identifier
- 9983966295302771
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