Thesis Format
Monograph
Degree
Master of Science
Program
Biochemistry
Supervisor
Duennwald, Martin
Abstract
Neurodegenerative diseases such as Parkinson’s disease and Amyotrophic Lateral Sclerosis have an unusually high proteostatic burden due to protein misfolding, leading to the disruption of mitochondrial homeostasis and the cellular proteostatic machinery. In this thesis, I investigate how oxidative stress and mitochondrial dysfunction intersect to drive the toxicity and aggregation of the disease-associated proteins CHCHD2/CHCHD10, TDP-43 and Alpha-Synuclein. I show that CHCHD2 and CHCHD10 form high-molecular weight aggregates under oxidative stress, with CHCHD2 showing increased mitochondrial localization. Next, TDP-43 toxicity was exacerbated in respiring cells but was mitigated by growth under caloric restriction conditions. The co-expression of mistranslating tRNAs further exacerbated TDP-43 toxicity in aging cells synergistically. These results uncover conserved stress pathways that regulate protein toxicity and aggregation relevant to neurodegenerative disease pathogenesis.
Summary for Lay Audience
Proteins are molecules within the cell that are made up of amino acids, and are responsible for the structure, function and proper regulation of the body’s cells and organs. In pathological states, these proteins become damaged or fold incorrectly, causing toxicity within the cell. Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS) are two progressive neurodegenerative diseases characterized by the misfolding, toxicity and accumulation of such misfolded proteins that interfere with normal cellular function in the brain.
My research aims to explore how various forms of stress within the cell, such as harmful oxygen species, disruptions in energy production, and protein synthesis errors, contribute to the toxicity of disease-linked proteins such as CHCHD2, CHCHD10, TDP-43, and Alpha-synuclein. I used yeast and human cell lines to mimic simplified disease-like environments and study the bidirectional relationship these proteins have with cellular dysfunction.
CHCHD2 and CHCHD10 are two mitochondrial proteins that assist with normal energy production within cells. I found that these proteins form large aggregates under oxidative stress, potentially as a result of disrupted protein bond formations. Impaired energy production also led to the increased transfer of CHCHD2 to the mitochondria, indicating that it is a stress responsive protein. I found that TDP-43, a protein commonly misregulated in ALS, showed increased toxicity in cells relying on mitochondrial respiration. I also saw increased TDP-43 toxicity when protein synthesis errors were introduced to aging cells, suggesting that these stressors can amplify its harmful effects. On the other hand, growing these cells in limited glucose helped mitigate this toxicity, which shows that certain metabolic adaptations can lead to better stress defenses.
My findings show that there are common mechanisms which underly neurodegeneration, such as oxidative stressors, mitochondrial dysfunction and protein misfolding. These findings can help inform future research aimed at developing protective strategies to prevent or slow disease progression in neurons.
Recommended Citation
Chugh, Nikita, "Oxidative stress and mitochondrial dysfunction in cellular models of neurodegeneration" (2025). Electronic Thesis and Dissertation Repository. 10868.
https://ir.lib.uwo.ca/etd/10868
Creative Commons License
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