Browsing by Subject "degeneration"

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    PKA phosphorylation of ATAXIN1 in Purkinje cells modulates early onset of ataxia
    (2017-01) Perez Ortiz, Judit
    Spinocerebellar ataxia type 1 (SCA1) is a fatal adult-onset, autosomal dominant ataxia characterized in part by dysfunction and degeneration of Purkinje cells of the cerebellum. The fundamental basis of pathology is an aberration in the regulation of RNA splicing and gene transcription. SCA1 is caused by an unstable CAG trinucleotide repeat mutation in the ATXN1 gene that codes for a toxic ATXN1 protein with an abnormal polyglutamine repeat. Decreasing mutant ATXN1 can reverse disease phenotypes in SCA1 mouse models. Phosphorylation of ATXN1 at Serine 776 (S776) is critical for disease and this modification influences ATXN1 protein levels and protein-protein interactions, which can exacerbate toxicity. Previous in vitro studies implicated PKA, cAMP protein kinase, in phosphorylation of ATXN1 at S776. The hypothesis being tested is that PKA-mediated ATXN1-S776 phosphorylation stabilizes ATXN1 and drives pathogenic pathways involved in disease. SCA1 mouse models expressing wild type human ATXN1[30Q] or mutant human ATXN1[82Q] were crossed to a PKA mutant mice that exhibit attenuated PKA activity. I found that PKA hypofunction leads to a decrease of phospho-S776-ATXN1 and total ATXN1 expressed in cerebellar Purkinje neurons. Mouse Atxn1 protein expressed in other cerebellar cell types was unchanged, pointing to cell specificity. In order to evaluate the disease relevance of these effects, I tested SCA1 disease metrics in the affected model, including motor behavior, histopathology and gene expression changes. Motor performance was improved to wild type levels early in disease, but progressive Purkinje cell atrophy was not averted. These results hinted at a dissociation between mechanisms causing ataxia versus Purkinje cell degeneration. Indeed, RNA sequencing studies revealed transcriptional changes linked to motor dysfunction that are distinct from those associated with progressive pathology. This work suggests ATXN1 is phosphorylated by PKA in Purkinje neurons early in disease and drives pathways that underlie early onset ataxia that are independent of pathways promoting progressive neurodegeneration.
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    Quantification of Intervertebral Disc Morphology: Alterations Associated with Age, Idiopathic Scoliosis, & Corrective Fusion Surgery
    (2022-08) Foltz, Mary
    Background: The intervertebral disc is altered naturally with aging, abnormally due to deformity, and mechanically due to surgery. Specifically, the structural integrity of the disc is altered, which may relate to the position of the nucleus pulposus (NP) with respect to the annulus fibrosus (AF). A typical, healthy disc has a centralized NP with a distinct transition to the AF (surrounds the NP). However, uncovering the altered morphology is not well understood. Objectives: The aims of this dissertation are: 1) characterize changes in disc morphology associated with age and degeneration in a back healthy cohort; 2) identify altered disc morphology and health in scoliotic discs compared to healthy controls; and 3) evaluate disc health and morphological alterations following corrective spinal fusion surgery. Methods: Following IRB approval, participants were enrolled (back healthy individuals and individuals diagnosed with adolescent idiopathic scoliosis). MRI (3T, Siemens, MAGNETOM) scans were then acquired. From sagittal images, qualitative degeneration of each disc was graded (based on the Pfirrmann scale). From axial images, quantitative degeneration of each disc was assessed via the NP signal intensity and signal volume. Additionally, the transition zone slopes (quantifying the distinction between the NP and AF) as well as the NP location were extracted from axial images, referred to as the disc morphology metrics. These disc health and morphology metrics were extracted from the MRIs to determine the change due to aging, scoliosis, and surgery. Results: Across the age spectrum, decreases in the transition zone slope magnitudes and anterior shift in the NP was observed with an increase in aging and disc degeneration. There was no change in the disc health metrics (NP signal intensity and signal volume) between control and scoliotic discs. In individuals diagnosed with scoliosis, the NP was located towards the convexity of the curvature and there was an increase in the convex transition zone slope compared to controls and the concave slopes. Following corrective spinal fusion surgery, there was no significant change in disc health or morphology metrics overtime (up to 2-years following surgery). However, there were significant differences between the adjacent and sub-adjacent disc levels for the disc health and morphology metrics (NP signal intensity, signal volume, transition zone slope, and NP location). Conclusions: Based on the MRI signal patterns, a shift in NP location along with altered transition zone slope magnitudes could be identified and provide information on underlying alterations to the structural integrity of the disc. Continued evaluation of the disc morphology through noninvasive MRI techniques may assist clinicians on patient specific treatment options.