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- Creators: School of Molecular Sciences
Description
Rett syndrome is a genetically based, X-linked neurodevelopmental disorder that affects 1 in 10,000 live female births. Approximately 95-97% of Rett syndrome cases are attributed to a mutation in the MECP2 gene. In the laboratory setting, key neuropathological phenotypes of Rett syndrome include small neuronal soma and nuclear size, increased cell packing density, and abnormal dendritic branching. Our lab previously created and characterized the A140V mouse model of atypical Rett syndrome in which the males are viable. Hippocampal and cerebellar granule neurons in A140V male mice have reduced soma and nuclear size compared to wild type. We also found that components of the mTOR pathway including rictor, 4E-BP-1, and mTOR, were reduced in A140V mutant mice. Quantitative PCR analysis also showed reduced IGFPB2 expression in A140V mice along with an upward trend in AKT levels that did not meet statistical significance. The objective of this study is i) to characterize the down regulation of AKT-mTOR pathway, and ii) to examine the effect of a genetic strategy to rescue mTOR pathway deficiencies in Mecp2 mutant mouse model. Genetic rescue of the mTOR pathway downregulation was done by crossing heterozygous female A140V mice with heterozygous male Tsc2 mice. Quantitative PCR analysis of A140V_Tsc2 RNA expression supported genetic rescue of mTOR pathway components, however, more testing is needed to fully characterize the rescue effect. Western blot analysis also showed reduction in phosphorylated AKT in Mecp2 A140V and T158A mutant mice, however, more testing is still needed to characterize the mTOR pathway in A140V_Tsc2 mice. Finally, other methods, such as a pharmacological approach, or transfection to increase mTOR pathway activity in cell lines, will be tested to determine if rescue of mTOR pathway activity ameliorate the Rett syndrome phenotype.
ContributorsGerald, Brittany Madison (Author) / Newbern, Jason (Thesis director) / Narayanan, Vinodh (Committee member) / Rangasamy, Sampath (Committee member) / School of Life Sciences (Contributor) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
As Alzheimer’s disease (AD) increases in incidence, there is an increased investigation into the pathogenesis of the disease in hopes of finding a cure to the neurodegenerative disease. The two key hallmarks of AD consist of amyloid beta plaques and hyperphosphorylated tau fibrillary tangles. Amyloid beta is a peptide that is proteolytically cleaved from the type I transmembrane glycolytic amyloid precursor protein (APP). APP is highly conserved across species, suggesting the importance of APP in healthy brain functioning. However, when APP is cleaved through the amyloidogenic pathway it produces amyloid beta. The trafficking of APP within neurons has been a new endeavor for neurodegenerative disease research, as reduced retrograde trafficking of APP has been hypothesized to increase the likelihood of the amyloidogenic cleavage of APP, resulting in increased amyloid beta presence (Ye et al., 2017). The findings of this study suggest that transport of APP within neurons is significantly inhibited by increased extracellular glutamate concentration. The addition of human primary astrocytes within a human neuron co-culture allowed for significantly increased retrograde transport of APP within neurons, even within high glutamate conditions. These finding enhance the current field of research regarding astrocytes neuroprotective role within the brain, but bring attention to the role that astrocytes have upon regulation of the axonal transport of proteins within neurons.
ContributorsKlosterman, Katja Elisabeth (Author) / Ros, Alexandra (Thesis director) / Redding, Kevin (Committee member) / Watts College of Public Service & Community Solut (Contributor) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2019-12