Current Search:  neurodegeneration (x)

View All Items

  • CSV Spreadsheet
(1 - 4 of 4)
INVESTIGATING THE ROLE OF NEURONAL AGING IN FRAGILE X-ASSOCIATED TREMOR/ATAXIA SYNDROME
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
IDENTIFICATION OF THE EFFECTS OF DIABETES MELLITUS ON THE BRAIN
Title
IDENTIFICATION OF THE EFFECTS OF DIABETES MELLITUS ON THE BRAIN.
Creator
Mikhail, Tryphina A, Samsam, Mohtashem, University of Central Florida
Abstract / Description
As more studies accumulate on the impact of diabetes mellitus on the central nervous system, they resound with the same conclusion - diabetes has a detrimental effect on cognition regardless of the presence of comorbidities. Less consistent however, are the specific mental processes wherein these declines are noticeable, and the structural changes that accompany these reductions in mental capacity. From global atrophy to changes in the volume of gray and white matter, to conflicting results...
Show moreAs more studies accumulate on the impact of diabetes mellitus on the central nervous system, they resound with the same conclusion - diabetes has a detrimental effect on cognition regardless of the presence of comorbidities. Less consistent however, are the specific mental processes wherein these declines are noticeable, and the structural changes that accompany these reductions in mental capacity. From global atrophy to changes in the volume of gray and white matter, to conflicting results regarding the effects of hypo- and hyperglycemic states on the development of the hippocampus, the studies display a variety of results. The goal of this research is to link the structural and compositional changes occurring in the diabetic brain with the clinical and behavioral findings highlighted in the literature, as well as to explore the potential mechanisms behind the pathologic brain state of diabetic encephalopathy. Using diabetic (OVE26) and non-diabetic wild type (FVB) mice as models, differences in the number of hippocampal neurons in the dentate gyrus, and cornu ammonis areas 1,2, and 3 were investigated through Nissl staining. Neurodegeneration was confirmed in those cells determined to be hyperchromatic in the diabetic model through staining with Fluoro-Jade C. Finally, the presence of progenitor cells in the hippocampus was compared in the diabetic and non-diabetic models using Musashi-1 antibodies, to determine whether neurogenesis in these areas is affected by diabetes. These experiments were performed to better understand the effect of DM on learning and memory, and could potentially explain the linkage between diabetes mellitus and the increased prevalence of Alzheimer�s disease, vascular dementia, and depression in this subset of the population.
Show less
Date Issued
2016
Identifier
CFH2000021, ucf:45601
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFH2000021
The Role of SOD1 Acetylation in Neurodegeneration
Title
The Role of SOD1 Acetylation in Neurodegeneration.
Creator
Kaliszewski, Michael, Bossy-Wetzel, Ella, Estevez, Alvaro, Kim, Yoon-Seong, Tatulian, Suren, University of Central Florida
Abstract / Description
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting motor neurons. Cu, Zn superoxide dismutase (SOD1), a cytoplasmic free radical scavenging enzyme, is mutated in familial ALS (fALS) and post-translational modification of the wild-type protein has been associated with sporadic ALS (sALS). Proteomic studies indicate that SOD1 is acetylated at Lys123; however, the role of this modification remains unknown. To investigate its function, we generated antibodies for...
Show moreAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting motor neurons. Cu, Zn superoxide dismutase (SOD1), a cytoplasmic free radical scavenging enzyme, is mutated in familial ALS (fALS) and post-translational modification of the wild-type protein has been associated with sporadic ALS (sALS). Proteomic studies indicate that SOD1 is acetylated at Lys123; however, the role of this modification remains unknown. To investigate its function, we generated antibodies for Lys123-acetylated SOD1 (Ac-K123 SOD1). Sod1 deletion in Sod1-/- mice, K123 mutation, or preabsorption with Ac-K123 peptide suppressed immunoreactivity, confirming antibody specificity. In the normal central nervous system, Ac-K123 SOD1 maps to glutamatergic neurons of the cerebellar cortex, dentate gyrus, hippocampus, olfactory bulb, and retina. In cultured neurons, Ac-K123 SOD1 localized to defined regions of axons and dendrites. Previous studies have suggested a role for SOD1 in cell cycle regulation. Therefore, we tested the distribution of Ac-K123 SOD1 during the cell cycle of astrocytes. In G1 Ac-K123 SOD1 localized to the nucleus, in G0 to the primary cilium, in metaphase and anaphase to chromosomes, and in telophase to the midbody. The deacetylase HDAC6 and acetyl-transferase ?-TAT1 are associated with the primary cilium. Therefore, we tested whether they regulate reversible acetylation of SOD1. HDAC6 knockdown or pharmacological inhibition markedly increased, while HDAC6 overexpression decreased, SOD1 Lys123 acetylation. By contrast, SOD1 Lys123 acetylation was decreased by ?-TAT1 knockdown and increased by ?-TAT1 overexpression. These results suggest that HDAC6 and ?-TAT1 regulate SOD1 Lys123 acetylation. Next, we examined Lys123 acetylation in fALS SOD1 mutants. Remarkably, Lys123 acetylation was dramatically increased in fALS mutants including SOD1 A4V. The acetyl-Lys123 mimetic of wild-type SOD1 caused axonal transport deficits similar to those observed in SOD1 pathogenic mutants such as A4V. Interestingly, HDAC6 deacetylation or acetylation resistance by Lys123 mutation, abolished A4V protein misfolding, axonal transport defects, and neuronal cell death. These results suggest that Lys123 acetylation plays a key role in the neurotoxicity of fALS mutants and may have implications in sALS. Because Ac-K123 SOD1 maps to the primary cilium, we examined whether ciliogenesis is altered in fALS mutant SOD1 astrocytes. Strikingly, fALS mutants caused centriole and primary cilia proliferation with ciliary ectosome secretion. Notably, multiciliated ependymal cells in the brain ventricles and spinal cord central canal, which are critical for cerebral spinal fluid circulation, stained strongly for Ac-K123 SOD1. Thus, we speculate that ciliary ectosome shedding from ependymal cells accounts for the presence of misfolded SOD1 in the CSF in fALS and perhaps sALS. In summary, we identified SOD1 Lys123 acetylation as a novel mechanism underlying protein misfolding and neurodegeneration in ALS. Ac-K123 SOD1 may emerge as novel target for the diagnosis and treatment of ALS.
Show less
Date Issued
2016
Identifier
CFE0006467, ucf:51409
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0006467
Development of human and rodent based in vitro systems toward better translation of bench to bedside in vivo results
Title
Development of human and rodent based in vitro systems toward better translation of bench to bedside in vivo results.
Creator
Berry, Bonnie, Hickman, James, Khaled, Annette, Lambert, Stephen, Sugaya, Kiminobu, University of Central Florida
Abstract / Description
Prospective medicinal compounds progress through multiple testing phases before becoming licensed drugs. Testing of novel compounds includes a preclinical phase where the potential therapeutic is tested in vitro and/or in animal models in vivo to predict its potential efficacy and/or toxicity in humans. The failure of preclinical models to accurately predict human drug responses can lead to potentially dangerous compounds being administered to humans, or potentially beneficial compounds being...
Show moreProspective medicinal compounds progress through multiple testing phases before becoming licensed drugs. Testing of novel compounds includes a preclinical phase where the potential therapeutic is tested in vitro and/or in animal models in vivo to predict its potential efficacy and/or toxicity in humans. The failure of preclinical models to accurately predict human drug responses can lead to potentially dangerous compounds being administered to humans, or potentially beneficial compounds being kept in development abeyance. Moreover, inappropriate choice in model organism for studying disease states may result in pushing forward inappropriate drug targets and/or compounds and wasting valuable time and resources in producing much-needed medications. In this dissertation, models for basic science research and drug testing are investigated with the intention of improving current preclinical models in order to drive drugs to market faster and more efficiently. We found that embryonic rat hippocampal neurons, commonly used to study neurodegenerative disease mechanisms in vitro, take 3-4 weeks to achieve similar, critical ion-channel expression profiles as seen in adult rat hippocampal cultures. We also characterized a newly-available commercial cell line of human induced pluripotent stem cell-derived neurons for their applicability in long-term studies, and used them to develop a more pathologically relevant model of early Alzheimer's Disease in vitro. Finally, we attempted to create an engineered, layered neural network of human neurons to study drug responses and synaptic mechanisms. Utilization of the results and methods described herein will help push forward the development of better model systems for translation of laboratory research to successful clinical human drug trials.
Show less
Date Issued
2015
Identifier
CFE0006261, ucf:51031
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0006261