Current Search: Southwell, Amber (x)
View All Items
- Title
- INVESTIGATING THE ROLE OF THE GUT MICROBIOME IN HUNTINGTON DISEASE.
- Creator
-
Hart, Casey G, Southwell, Amber, University of Central Florida
- Abstract / Description
-
Huntington disease (HD) is an inherited neurodegenerative disease caused by a trinucleotide repeat expansion in the huntingtin (HTT) gene. Metabolic dysfunction is a feature of HD that is recapitulated in HD mouse models. Our lab has shown that circadian feeding rhythms are disrupted in humanized HD mice and restored by suppression of brain HTT. Furthermore, when circadian feeding rhythm is artificially restored, in addition to normalization of metabolic function, liver and striatal HTT is...
Show moreHuntington disease (HD) is an inherited neurodegenerative disease caused by a trinucleotide repeat expansion in the huntingtin (HTT) gene. Metabolic dysfunction is a feature of HD that is recapitulated in HD mouse models. Our lab has shown that circadian feeding rhythms are disrupted in humanized HD mice and restored by suppression of brain HTT. Furthermore, when circadian feeding rhythm is artificially restored, in addition to normalization of metabolic function, liver and striatal HTT is temporarily reduced, demonstrating that HTT is involved in gut-brain feedback. The gut microbiome, which can regulate gut-brain feedback, has been implicated in the pathogenesis of other central nervous system disorders and we hypothesize it also plays a role in HD. The objective of this study is to investigate alterations in relative abundance of HD gut microbiota using existing plasma metabolomics data to identify candidate bacteria. If distinct microbiota profiles are demonstrated, this would provide the basis for future unbiased studies to investigate the complete HD microbiome.
Show less - Date Issued
- 2018
- Identifier
- CFH2000418, ucf:45814
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFH2000418
- Title
- INVESTIGATING THE ROLE OF THE CASPASE-6 CLEAVAGE FRAGMENT OF MUTANT HUNTINGTIN IN HUNTINGTON DISEASE PATHOGENESIS.
- Creator
-
McKinnis, Jourdan A, Southwell, Amber, University of Central Florida
- Abstract / Description
-
Huntington disease (HD) is a devastating and fatal neurodegenerative disease. At the moment, no disease modifying therapies are available, with only symptomatic treatment offered to alleviate psychiatric and some types of motor deficits. As a result, many people will continue to suffer and die from this disease. Small molecule therapies have failed to provide benefit in HD, necessitating more complex gene therapy approaches and the identification of less traditional therapeutic targets. A...
Show moreHuntington disease (HD) is a devastating and fatal neurodegenerative disease. At the moment, no disease modifying therapies are available, with only symptomatic treatment offered to alleviate psychiatric and some types of motor deficits. As a result, many people will continue to suffer and die from this disease. Small molecule therapies have failed to provide benefit in HD, necessitating more complex gene therapy approaches and the identification of less traditional therapeutic targets. A previous study demonstrated that preventing cleavage of the huntingtin (HTT) protein, the protein that when mutated causes HD, by caspase 6 (C6) at amino acid 586 prevents the onset of disease in transgenic HD model mice. This suggests that inhibiting the toxicity initiated by N586 cleavage could be a promising therapeutic strategy, but a safe and specific way to do this in humans has not been identified. General C6 inhibition is not a feasible strategy due to the vital functions it plays throughout life. Thus, the purpose of this study was to investigate whether the C6 cleavage fragment of HTT, N586, is itself a toxic species of HTT or if it initiates a toxic proteolytic pathway in order to identify more viable therapeutic strategies for HD. To accomplish this, we are using novel and highly sensitive immunoprecipitation and flow cytometry (IP-FCM) protein detection assays, specific for the N586 neoepitope of HTT, to evaluate the in vivo persistence of N586 in HD model mice. If N586 is detected, it is likely that it is itself toxic and promoting its degradation may be beneficial. Conversely, if it is not detected, N586 cleavage likely initiates a toxic degradation pathway and promoting its stability may be beneficial. The results of these studies have the potential to define new therapeutic strategies for HD that can be addressed more specifically than generalized C6 inhibition for the prevention of N586-mediated toxicity. The selective targeting of N586 toxicity, either to promote or prevent its degradation depending on our results, would ensure that therapeutic activity is restricted to HTT and reduce the potential for deleterious off-target effects
Show less - Date Issued
- 2018
- Identifier
- CFH2000395, ucf:45801
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFH2000395
- Title
- INVESTIGATING THE ROLE OF NEURONAL AGING IN FRAGILE X-ASSOCIATED TREMOR/ATAXIA SYNDROME.
- Creator
-
Hencak, Katlin Marie, von Kalm, Laurence, Southwell, Amber, University of Central Florida
- Abstract / Description
-
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an X-linked late-onset neurodegenerative disorder caused by a noncoding trinucleotide repeat expansion in the FMR1 gene. This gene produces fragile x mental retardation protein (FMRP), an RNA binding protein whose targets are involved in brain development and synaptic plasticity. One of the proposed mechanisms of FXTAS pathogenesis is an RNA gain-of-function in which the repeat expansion causes toxic mRNA that sequesters important...
Show moreFragile X-associated tremor/ataxia syndrome (FXTAS) is an X-linked late-onset neurodegenerative disorder caused by a noncoding trinucleotide repeat expansion in the FMR1 gene. This gene produces fragile x mental retardation protein (FMRP), an RNA binding protein whose targets are involved in brain development and synaptic plasticity. One of the proposed mechanisms of FXTAS pathogenesis is an RNA gain-of-function in which the repeat expansion causes toxic mRNA that sequesters important proteins in the cell, interfering with their functions. Another suggested method of pathogenesis is through a mutant protein called FMRpolyG. This protein results from repeat-associated non-AUG (RAN) translation, in which the expanded repeats are translated where they otherwise would not be. This protein co-localizes with intranuclear inclusions and nuclear membrane proteins, causing disorganization of the nuclear lamina in FXTAS patient brain samples and neurons differentiated from FXTAS patient-derived induced pluripotent stem cells (iPSCs). iPSC technology involves reprogramming an adult somatic cell back to an embryonic-like state, allowing it to be differentiated into all cell types. A limit with iPSCs, though, is modeling late-onset disorders because the cells lose all age-related features during reprogramming. Progerin, a truncated form of the lamin A protein, has been used to age neurons differentiated from Parkinson Disease (PD) patient-derived iPSCs. Progerin-mediated aging was found to unmask PD-like phenotypes in those neurons, making it a promising technology for modeling late-onset disorders such as FXTAS. In this study, we investigated the link between the aging process and FXTAS pathogenesis in neurons differentiated from FXTAS patient-derived iPSCs with the use of progerin. Progerin transduction was successful in aging the FXTAS neurons. The presence of FMRpolyG was confirmed and an interaction with Lap2b was observed. In some neurons, there was also an observed interaction between FMRpolyG and progerin. Overall, this data suggests that there is an interaction between the mutant FMRpolyG protein and the nuclear membrane during aging, which may contribute to the cell death that causes neurodegeneration in FXTAS patients.
Show less - Date Issued
- 2019
- Identifier
- CFH2000554, ucf:45678
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFH2000554