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Authors: Caponiti, Julia M.
Advisors: Gould, Elizabeth
Contributors: Psychology Department
Keywords: amyotrophic lateral sclerosis
motor neuron
neurodegenerative disease
Subjects: Neurosciences
Molecular biology
Issue Date: 2012
Publisher: Princeton, NJ : Princeton University
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes widespread motor neuron degeneration in the brain and spinal cord and eventually leads to paralysis and death. Although most motor neurons are vulnerable to ALS, a few groups survive until late stages of the disease. The oculomotor nucleus (OMN), which innervates the eye muscles, and Onuf's nucleus, which innervates the muscles of the penis and anal sphincter, are both resistant to degeneration in ALS (Mannen et al., 1977; Alexianu et al., 1994). The rodent homologue of Onuf's nucleus is the spinal nucleus of the bulbocavernosus (SNB). Like ALS patients, ALS transgenic rodent models exhibit less cell death in the OMN and SNB than in other motor neuron populations (Nimchinsky et al., 2000; Hamson et al., 2002). My dissertation research is aimed at exploring differences in gene expression between motor neurons that are resistant to degeneration and those that are vulnerable to degeneration with the ultimate goal of identifying genes that can be further explored for their ability to protect against ALS-induced death. To examine gene expression in motor neurons with differential susceptibility to ALS, I used microarray analysis on the two resistant motor neuron populations (OMN, SNB) compared to two vulnerable motor neuron populations - the trigeminal nucleus (TGN), which innervates face and mouth muscles, and the retrodorsolateral nucleus (RDLN), which innervates the foot muscles. Multiple genes with differential expression between resistant and vulnerable motor neuron populations were identified. After stringent statistical analyses, there were 47 genes with higher expression in the resistant motor neurons and 42 genes with higher expression in the vulnerable motor neurons. Two of these genes were selected for further investigation based on their known functions. Brain expressed, X-linked 1 (Bex1) had greater expression in the resistant motor neuron populations, and ribosomal protein s6 kinase, polypeptide 5 (Rps6ka5 or Msk1) had greater expression in the vulnerable motor neurons. I verified the expression patterns of these genes using confocal optical intensity analyses of immunolabeled tissue and western blots to ensure that the differences in gene expression translated into differences in protein expression. BEX1 and MSK1 were then investigated at a presymptomatic time point in a rodent model of ALS (mutant SOD1G93A transgenic rats) using confocal optical intensity analyses. BEX1 had significantly greater expression in the resistant motor neurons than the vulnerable motor neurons in both the transgenics and the wildtypes, with no significant differences between the two groups of animals. It is possible that BEX1 would be further upregulated after the onset of symptoms, or that it is a protective mechanism that is not modified by the disease process itself. MSK1 had significantly greater expression in the vulnerable motor neurons than the resistant motor neurons, with no difference between groups in the brainstem. However, the wildtype rats had greater MSK1 expression in the spinal cord than the transgenics. It is possible that the disease process does not affect all populations of motor neurons equally. Future studies will need to investigate the expression of BEX1 and MSK1 in later stages of the disease process to fully understand how the disease affects expression levels. Bex1 and Msk1 might be suitable targets for gene therapy to modify neuronal survival within the ALS-vulnerable populations of motor neurons. Because the death of motor neurons is a hallmark of ALS, understanding how some motor neuron populations resist degeneration, even in the late stage of the disease, is critical for advancing the treatment of ALS.
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Psychology

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