Browsing by Subject "Spinocerebellar Ataxia"
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Item Defining a Neuroprotective Pathway for the Treatment of Ataxias(2016-08) Leathley, EmilySpinocerebellar Ataxias (SCAs) are a group of genetic diseases characterized by progressive ataxia caused by neurodegeneration of specific cell types, namely Purkinje Cells (PCs) of the cerebellum. Mouse models of SCA Type 1 (SCA1) can be used to study the molecular mechanisms underlying PC degeneration and death. One SCA1 mouse model, ATXN1[30Q]D776, has an initial ataxia but no progressive degeneration or PC death. RNA-seq experiments identified the up-regulation in the cerebellum of the peptide hormone Cholecystokinin (Cck) in these mice. Knocking out Cck or the Cck1 receptor (Cck1R) in ATXN1[30Q]D776 mice confers a progressive disease where PC death occurs by thirty-six weeks of age. Weighted Gene Co-expression Network Analysis (WGCNA) performed on cerebellar RNA-seq data from ATXN1[30Q]D776;Cck-/- mice identified a disease progression-related gene set named the Pink Module that is influenced by Cck. A Cck1R agonist, A71623, was administered via osmotic minipump to ATXN1[30Q]D776;Cck-/- mice and AXTN1[82Q] mice, which are a more faithful representation of human SCA1 PC degeneration. In both mouse models, A71623 protected against progressive ataxia and PC degeneration. These results suggest that manipulation of the Cck-Cck1R pathway may be a therapeutic target for treatment of diseases involving PC degeneration.Item Identifying Senescence in Tissues Affected by Spinocerebellar Ataxia Type 7(2021-06) Pruett, Charles LewisBackground: Spinocerebellar Ataxia Type 7 (SCA7) is an age-related neurodegenerative disease caused by a trinucleotide CAG repeat. SCA7 predominantly causes a loss of photoreceptors of the retina and Purkinje cells of the cerebellum, but severe forms also cause renal and cardiac irregularities. Previous reports have shown that SCA7 results in increased susceptibility to DNA damage. Increased DNA damage can lead to an accumulation of senescent cells, which is known to contribute to other age-related diseases. Hypothesis: SCA7 causes an accumulation of senescent cells in affected tissues over the course of disease. Methods: A 266 CAG SCA7 mouse model was evaluated for renal and cardiac dysfunction in addition to previously described metabolic and neurologic problems. Senescence was evaluated in the kidneys and cerebellum of these mice via RT-qPCR for the cell cycle inhibitors p16 and p21 and staining for SA-ßgal Results: Senescent cells accumulate in the kidneys of these mice throughout the course of disease. The Purkinje layer in the cerebellum of the SCA7 mice display increased SA-ßgal staining, potentially displaying a senescent-like phenotype.Item The role of gene expression and aging in SCA1(2013-12) Ingram, Melissa Anne CornwellSpinocerebellar 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.