Date of Award


Document Type

Open Access Thesis


Biomedical Science


School of Medicine

First Advisor

Norma Frizzell


Leigh syndrome is the most common mitochondrial disease, affecting 1:40,000 live births. It manifests with symptoms including ataxia, cognitive impairment, motor difficulties, and stroke. Leigh syndrome is a genetic condition caused by mutations in either the nuclear DNA or mitochondrial DNA that affects the assembly of the electron transport chains. Death typically occurs around 2-3 years of age, due to respiratory failure, as the body cannot produce sufficient ATP for survival. The genetic basis of Leigh syndrome means that there is no cure, and current treatments of the symptoms have proven ineffective. This thesis proposes two different therapeutic approaches for Leigh syndrome. The Ndufs4 knock-out (KO) mouse is an animal model of Leigh syndrome, and is the result of a mutation in complex I of the electron transport chain. This leads to symptoms almost identical to human patients including necrotizing lesions, seizures and motor impairments. The pathology in this model is associated with oxidative stress, protein succination, and inflammation. The therapeutic interventions selected are aimed at reducing these factors and the role that they play in disease progression.

N-acetylcysteine amide (NACA) is a precursor for glutathione, a powerful cellular antioxidant involved in the reduction of oxidative stress. In this study we administered NACA for 14 days and examined the effect on motor coordination in the mice. In addition, we examined the levels of a protein modification (protein succination) that is derived from the reaction of fumarate with protein thiols and is increased in the affected brain regions. We observed an improvement in the fine motor coordination in the mice receiving NACA for 14 days, highlighting the potential utility of this treatment; however, we did not detect reductions in oxidative stress markers or protein succination in association with this improvement.

Patients with Leigh syndrome display increased neuroinflammation and, in a similar manner, the Ndufs4 KO mouse also displays increased immune cells, particularly microglia, congregated in and around these lesions. PLX5622 is a microglial depletion drug and we hypothesized that decreasing the microglial content would decrease the inflammation, and contribute to improved survival and behavioral improvements. We also proposed that it may reduce protein succination in the brainstem as increased succination has recently been associated with macrophage activation. Overall, PLX5622 administration did not appear to be beneficial for the course of the pathology in the Ndufs4 KO mice, perhaps in part due to the severity of their symptoms and the need for some functional microglial presence to remove dying neurons.


© 2018, Stephanie Martin