The role of gene expression and aging in SCA1
2013-12
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The role of gene expression and aging in SCA1
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2013-12
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Spinocerebellar ataxia type 1 is an autosomal dominant disorder caused by a CAG repeat expansion encoding a polyglutamine tract, where patients present with a lack of motor coordination including ataxia. The disease is characterized pathologically by loss of Purkinje cells (PCs) in the cerebellar cortex and neuronal loss in brain stem nuclei and cerebellar dentate nuclei. Besides expansion of the polyglutamine tract, other features of ATXN1 are critical for pathogenesis and severity of disease including phosphorylation of ATXN1 at S776. Mouse models expressing an expanded form of ATXN1, ATXN1[82Q] share initial disease features, such as ataxia, with mice with a normal repeat length with a phosophomimetic aspartic acid substitution, ATXN1[30Q]-D776. However, ATXN1[30Q]-D776 mice do not display late-stage, progressive disease features including PC death. In order to determine molecular pathways leading to the ataxic similarities as well as progressive disease differences in the models, I used RNA-sequencing to examine the cerebellar transcriptome. In addition to identifying candidate genes, Col18a1 and Cck, involved in PC - climbing fiber dynamics, I found splicing correlates with ataxia in the ATXN1[82Q] and ATXN1[30Q]-D776 mice. In order to validate RNA-seq targets and focus on the more biologically relevant splicing candidates, I developed and analyzed RNA-seq from a conditional ATXN1[30Q]-D776 model. In addition, I used this model to examine disease recovery. Interestingly, I found a lack of recovery at older ages without PC death, suggesting older neurons are inherently less able to recover.
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University of Minnesota Ph.D. dissertation. December 2013. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: Nikunj V. Somia. 1 computer file (PDF); viii, 136 pages,appendix 1.
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Ingram, Melissa Anne Cornwell. (2013). The role of gene expression and aging in SCA1. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/162494.
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