Date of Award

2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

Abstract

Amyotrophic Lateral Sclerosis (ALS) is the most common adult motoneuron (MN) degenerative disease. Discovery of a portion of familial cases with a mutation in the gene superoxide dismutase 1 (SOD1) gene led to the development of a transgenic mouse model. Pre-symptomatic SOD1 mice show no symptoms well into adulthood, however once symptom onset has occurred they display pathological hallmarks of ALS. The initial pathological event is loss of neuromuscular junctions in the lower limbs and therefore the die-back theory of ALS, suggests disconnection from the target musculature leads to MN degeneration. Our lab utilizes a peripheral nerve injury model to investigate the mechanisms of MN survival in the pre-symptomatic SOD1 mouse. We have shown SOD1 mice display enhanced facial MN (FMN) cell loss following a facial nerve axotomy, compared to wild-type (WT) mice. Analysis of gene expression revealed that MN regenerative genes were expressed to a similar extent in SOD1 and WT mice however, differences were seen among genes expressed by the neuropil, namely pro-inflammatory genes and suppression of the astrocytic response. Experiments within this dissertation evaluated whether axotomy-induced molecular response in pre-symptomatic SOD1 mice, resembles the disease-induced molecular response within the facial nucleus in symptomatic SOD1 mice. This dissertation identified that microglia show abnormal, suppressed responses to axonal injury. In addition, while increased expression of death receptor genes is a reaction to MN injury in both WT and SOD1 mice initially, however, Fas death receptor genes are dysregulated in the SOD1 axotomized facial nucleus at a time consistent with enhanced FMN loss. Most importantly, the increased mRNA expression seen in the SOD1 disease-affected nucleus during the symptomatic stage is consistent with the mRNA expression response after axotomy in pre-symptomatic SOD1 mice. The work presented within this dissertation concludes that the molecular response within the SOD1 facial nucleus is similar regardless of the method MN injury (axotomy/disease) and therefore, allows for axotomy to be used in the pre-symptomatic mouse as a model of disease progression.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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