Access Type

Open Access Dissertation

Date of Award

January 2017

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Molecular Biology and Genetics

First Advisor

Alexander Gow

Abstract

The work of this project was to develop, test and characterize a potential novel mouse model of the neurodegenerative disease Multiple Sclerosis (MS). Historically, MS has been identified as a primary autoimmune disease of the central nervous system (CNS). However, treatments based on this view have met with limited success, and in most cases, fail to prevent progression of MS from mild to moderate and severe forms. Original observations regarding axonal and neuronal pathology in the white and gray matter of the CNS were rediscovered in the 1990s. These observations indicated that even in the absence of the immune system, degeneration can be widespread throughout the CNS. In addition, observations on the demyelinating leukodystrophy Pelizaeus-Merzbacher Disease (PMD), that could present with MS-like symptoms led to a new hypothesis on the etiology of MS.

This hypothesis was that primary metabolic stress in oligodendrocytes could be contributing to the etiology and pathology of MS. To test this, our lab developed the OBiden model, where we can induce metabolic stress in mature, myelinating oligodendrocytes. The method of metabolic stress induction is well characterized and therefore allows for the study of the secondary behavioral and neurodegenerative changes that occur in the OBiden mouse.

The OBiden mouse was found to develop a depression-like endophenotype at 6 months of age that persisted through until 12 months of age. Deficits in working and novel memory also developed at 12 months of age, and both behavioral changes are analogous to those noted in MS patients. Next, secondary lesions in white matter as well as extensive gliosis were identified in the OBiden animals, both of these results match closely with observations on MS tissue. Finally, secondary gray matter changes were noted throughout the CNS, specifically in cortical and hippocampal areas closely associated with the noted behavioral decline. These changes included structural neurofilament alterations and the novel identification of changes to the proximal axon called the axon initial segment (AIS). The AIS is intimately associated with action potential generation and changes to AIS structure or function are noted to coincide with neuronal firing changes. These neuronal changes are likely the cause of the behavioral deficits noted in the OBiden mice and develop solely as a secondary result to the primary oligodendrocyte stress.

Together, these results indicate that the OBiden mouse shares a number of similarities to MS patients including cognitive behavioral changes and molecular degeneration phenotypes. These degenerative consequences occur without the invasion of the peripheral immune system and instead are a result of primary metabolic stress in oligodendrocytes. Therefore, the OBiden mouse may represent a novel insight into MS pathology and allow more general research into the communication and interaction between oligodendrocytes and neurons.

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