June 2011

Document Type


Degree Name



Oregon Health & Science University


Though multiple sclerosis (MS) has traditionally been considered an inflammatory disease, recent evidence has brought neurodegeneration to the spotlight, suggesting that axonal and neuronal injury and loss are important factors in disease progression. Various mechanisms have been proposed to address the neurodegenerative component in MS, which all at some level posit cytosolic and subsequent mitochondrial Ca[superscript 2+] overload, generation of reactive oxygen species (ROS), and ensuing mitochondrial dysfunction as precipitating factors. Previous studies have shown that mutational inhibition in mice of a mitochondrial Ca[superscript 2+] and ROS efflux pathway, the permeability transition pore (PTP), results in resistance to the axonal degeneration that accompanies the murine model of MS, experimental autoimmune encephalomyelitis (EAE). These studies point to PTP activation as a key player in the degenerative mechanisms that occurs in EAE, and potentially MS. In an effort to elucidate the pathways leading to PTP activation and mitochondrial dysfunction in EAE, the role of a potential upstream effector was investigated. Notably, p66ShcA (p66) has recently been discovered as a redox enzyme that regulates mitochondrial ROS levels by oxidizing cytochrome C and catalyzing the reduction of oxygen to hydrogen peroxide. Oxidative insults induce p66 mitochondrial translocation and accumulation of active enzyme within the intermembrane space. Utilizing the murine disease model EAE, p66-knockout (p66-KO) and WT mice were immunized with myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide. The results demonstrated that p66-KO mice developed EAE, but had less severe clinical impairment and paralysis compared to WT mice. Histologic examination of spinal cords and optic nerves showed significant tissue and axonal protection in the p66-KO mice despite similar levels of inflammation as reported by immunohistologic studies, T-cell proliferation, and cytokine assays. Furthermore, neuronal cultures derived from p66-KO mice were more resistant to reactive oxygen and nitrogen species implicated in neurodegenerative pathways of EAE and MS. This resistance was correlated with greater preservation of mitochondrial integrity in p66-KO neurons as indicated by less altered mitochondrial morphology and mitochondrial ROS levels following oxidative insults. Interestingly, however, mitochondrial transport was in general similarly decreased in both p66-KO and WT neurons, suggesting that p66 elimination has no direct effect on transport mechanisms. Overall, these results provide additional evidence that inactivation of mediators of mitochondrial PTP opening confers axonal and neuronal protection. Hence, in addition to mitochondrial PTP- and ROS-targeted drugs, pharmacologic p66 inhibitors may represent a new approach to neuroprotection in MS therapy.




Neuroscience Graduate Program


School of Medicine



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