UBC Theses and Dissertations
The effect of remyelination blockade on axon survival and damage in experimental autoimmune encephalomyelitis Brown, Douglas Robert
Multiple sclerosis is the most common cause of neurologic disability in the developed world. A heterogeneous disease of unknown cause that most often presents in mid life, it is characterized by years of relapsing and remitting symptoms that eventually become progressive. The pathology of Multiple Sclerosis is characterized by resolving and non-resolving neurological deficits caused by axonal dysfunction and degeneration, which are mediated by both inflammation and demyelination. Remyelination is an intrinsic myelin repair mechanism that replaces lost myelin in response to demyelination and mitigates its pathological effects. Experimentally, remyelination has been shown to promote axon survival in inflammatory demyelination contexts, however, it is unknown if blocking remyelination will result in increased axon loss and damage. Determining the importance of remyelination for axon preservation is necessary to determine the efficacy of remyelination therapies. Assessing the effect of blocked remyelination is an important part of this picture. To determine this we used the rodent model of MS, Experimental Autoimmune Encephalomyelitis (EAE), to initiate demyelination, and blocked remyelination by inducibly deleting the gene Myelin Gene Regulatory Factor (Myrf) using the Cre-lox gene editing system. We then assessed axon survival and damage, myelination state, EAE disease severity and progression, microglial activation, and dorsal column size in the lumbar spinal cord of affected mice. We found that blocked remyelination did not affect axon survival or damage, but delayed EAE disease onset, reduced myelin in the ventral white matter and increase activation of microglia in affected areas. Strictly interpreted, our results suggest that remyelination may not be as important for axon survival as hypothesized. However, non-statistically significant trends in the results (Axon Loss p = 0.11 and Axon damage p = 0.15 in ventral/dorsal white matter combined) suggest that the lack of effect seen here may have been due to limitations and unforeseen problems encountered during these experiments. Unfortunately, these casts some doubt on our findings, but may highlight some previously unknown difficulties and effects such as delayed EAE induction and increased disease severity that may have been unintended consequences of the Myrf knock out, indicating that more investigation is warranted.
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