Theses and Dissertations at Montana State University (MSU)
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Item Investigations of the gut-brain-metabolism axis in familial dysautonomia(Montana State University - Bozeman, College of Letters & Science, 2023) Cheney, Alexandra Marie; Co-chairs, Graduate Committee: Frances Lefcort; Valerie Copie; This is a manuscript style paper that includes co-authored chapters.Familial dysautonomia (FD), a neurodevelopmental and neurodegenerative disease primarily present in Eastern European Jewish populations, is a useful model system to explore the effects of neuronal dysregulation, particularly in the developing field of the gut-brain-metabolism axis. FD originates from a single genetic mutation in the ELP1 gene and differs from other neurological diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and autism that are dependent on multiple factors. Metabolic and gut impairments have been observed in FD patients, but only symptom management has been pursued without further exploration into the underlying disease pathophysiology. To better understand how the gut environment changes as a result of neuronal dysregulation and how this impacts the gut-brain-metabolism axis in FD patients, several studies of both human and FD mouse model samples were undertaken. Serum and stool samples from FD patients and their relatives were analyzed for metabolic alterations using proton nuclear magnetic resonance (1H NMR)-based metabolomics. Stool samples from both a human cohort and FD mice were also analyzed for gut bacterial diversity via 16S rRNA gene sequencing. Additionally, stool metabolomes of FD mice were analyzed for metabolic alterations. The FD mouse model enabled us to explore how gut physiology changed during disease progression using gut histological methods and gut function assays. Our studies demonstrated significant changes in the metabolomes and gut microbiomes of FD patients compared to their healthy relative controls. Additionally, the FD mouse model, a pan-neuronal Elp1 conditional knock out, was sufficient to drive metabolic and gut microbiome changes, and impair gut barrier function compared to control mice. When FD mice cohabitated with healthy control mice and were able to exchange gut microbes via stool consumption, the cohoused FD mice improved in overall health and gut function. Our studies found that the gut microbiome and metabolome of cohoused FD mice were comparable to their cohoused control counterparts. Overall, this work has enhanced our understanding of the gut-brain-metabolism axis in Familial dysautonomia and has provided insights into underlying molecular mechanisms, which may be potential targets for therapeutic interventions, including the use of metabolic supplements and/or altering the gut microbiome.Item Investigation of the cellular pathology underlying the optic neuropathy in a mouse model of familial Dysautonomia(Montana State University - Bozeman, College of Agriculture, 2023) Schultz, Anastasia Mardell; Chairperson, Graduate Committee: R. Steven Stowers; This is a manuscript style paper that includes co-authored chapters.Familial dysautonomia (FD) is a rare, recessive, progressive autosomal disorder that affects the nervous system. This neurological disorder is caused by a splice mutation in the Elongator complex I (ELP1) gene. The mutation results in a tissue-specific reduction of ELP1 protein due to unstable mRNA targeted for nonsense-mediated decay. ELP1 is a highly conserved scaffolding protein and core subunit of the six-subunit Elongator complex required for normal translation, neuronal development, and survival. Insufficient ELP1 leads to the developmental death of neurons in the peripheral and autonomic nervous systems in addition to central and peripheral nervous system neurodegeneration. Patients suffer from congenital and progressive neuropathies, such as cardiovascular dysfunction, reduced peripheral sensory function, poor growth, and digestive and respiratory problems. Outside of the risk of death in early adulthood, one of the most debilitating conditions affecting patients' quality of life is progressive blindness marked by continual loss of retinal ganglion cells (RGCs). Within the FD community, there is a concerted effort to develop treatments to prevent the loss of RGCs, thereby improving patients' quality of life. This study aims (1) to elucidate mechanisms underlying the death of RGCs in the absence of Elp1 and (2) to obtain pre-clinical intervention data that can eventually be translated into therapeutics for rescuing RGCs in FD. Using histology and confocal microscopy in conjunction with biochemistry, this study provides evidence for disrupted cellular homeostasis and inflammation preceding RGC death, and as the disease progresses, the retinal cells fail to mount a correct stress response to restore neuronal homeostasis. Furthermore, this study provides first-of-its-kind pre-clinical data using targeted gene therapies to rescue RGCs. Understanding the biological crosstalk and signaling mechanisms underlying the death of RGCs in the absence of Elp1 will allow for more targeted and effective therapeutics that will benefit not only the FD community but also individuals affected by other retinal diseases and neurological diseases that result from a faulty Elongator complex. This study provides a novel characterization of the FD retina and establishes baseline methods to further investigate rescuing RGCs.Item Evaluation of innate anxiety in Ta1tubulin-cre/Ikbkap -/- mice : the effects of the IKAP protein deletion from the central nervous system(Montana State University - Bozeman, College of Letters & Science, 2014) Kujawa, Katharine Jacobs; Chairperson, Graduate Committee: A. Michael BabcockFamilial Dysautonomia (FD) is a hereditary sensory and autonomic neuropathy (Type III) marked by a mutation within the Ikbkap gene encoding the IKAP protein. This mutation is prevalent in 99% of the clinical FD population (Shobhat & Halpern, 2010). Symptoms include emotional labiality, cardiovascular instability, vomiting crises and decreased pain and temperature sensation. One clinical symptom associated with FD is increased anxiety in response to stressful situations (Axelrod, 2006). Dr. Lefcort in the department of Biology and Neuroscience at Montana State University has generated a novel mouse model of FD in which Ikbkap is selectively deleted from CNS neurons. The present study characterized the expression of anxiety behaviors in this mouse model using a standard elevated plus maze task. It was observed that FD mice spent significantly more time in the open arms relative to control mice. These mice exhibited significantly greater instances of unprotected head-dipping and fewer protected head-dipping compared to controls. The FD mice also traveled slower than controls but time immobile and distances traveled were found to be similar. These data suggest that the FD mice presented as less anxious, an observation that is inconsistent from observations in the clinical population. Additional research aimed at characterizing the behavioral phenotype of these mice is under investigation.Item Analysis of the central nervous system in a mouse model of HSAN Type III(Montana State University - Bozeman, College of Letters & Science, 2013) Waller, Hannah Rose; Chairperson, Graduate Committee: Frances LefcortFamilial Dysautonomia (FD), also called Riley Day Syndrome, is a Hereditary Sensory and Autonomic Neuropathy (HSAN Type III) that is characterized by dysfunction of the sensory and autonomic nervous systems. The disease is caused by a severe reduction in levels of the protein IKAP as a result of a point mutation in Ikbkap mRNA which results in targeting of the mRNA for nonsense mediated decay. In humans, symptoms include autonomic crises, tachycardia, blood pressure lability, lack of overflow tears, decreased pain and temperature sensation, and scoliosis. Half of affected individuals die by age 40. Although FD has been traditionally classified as a disease of the autonomic nervous system, there have been notable effects observed in the central nervous system (CNS) as well, though many of these observations remain to be quantified. The presented study evaluated the impact of FD on the CNS using a mouse model where Ikbkap was deleted selectively from neurons of the CNS. For this model, a conditional knockout (CKO) strategy was employed because mice that are null for Ikbkap die by embryonic day 10.5, precluding their usefulness for analyzing FD in the adult CNS. For this study, morphological analyses and immunohistochemical staining were performed on the brain tissue. Affected mice were found to have a significant reduction in choline acetyltransferase (ChAT) positive neurons in the dorsal motor nucleus of the vagus nerve (DMNX) relative to controls, indicating potential decreased parasympathetic innervation of the nucleus in the heart and other target organs. Additionally, the size of the lateral ventricles and hippocampus relative to hemisphere size was significantly increased for the mutant mice. Further, the corpus callosum and lateral amygdaloid nucleus areas were significantly decreased relative to wild-type controls. Cortical layering was found to be normal in Talpha1tubulin-Cre/Ikbkap CKO mice. Taken together, these results suggest that the morphological differences are associated with increased cell death and decreased neurogenesis and cell differentiation. The neural and morphological findings presented in this study are the first data demonstrating perturbations in the CNS of a mouse model for FD and may explain some of the phenotypes observed in FD patients.