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Exploring The Structure And Biochemistry Of Oxidation-Mediated Inhibitation Of The Peptidyl-Prolyl Isomerase Pin1, Brendan T. Innes Dec 2013

Exploring The Structure And Biochemistry Of Oxidation-Mediated Inhibitation Of The Peptidyl-Prolyl Isomerase Pin1, Brendan T. Innes

Electronic Thesis and Dissertation Repository

Pin1 is a phosphorylation-dependent peptidyl-prolyl isomerase that has been shown to be neuroprotective in aging-related neurodegenerative diseases such as Alzheimer's disease (AD). However, it is not active in AD brain, and a recent proteomic screen of Mild Cognitive Impairment (MCI) brain samples revealed that Pin1 is oxidized in the brains of these pre-AD patients. This suggests that this oxidation may be the cause of the loss of the neuroprotective Pin1 function in AD. The Pin1 active site contains a functionally critical cysteine residue (Cys113) with a low predicted pKa, making it highly susceptible to oxidation. We hypothesize that Pin1 ...


Studying Aggregate Formation By Amyotrophic Lateral Sclerosis-Associated Mutant Sod1 Protein In Drosophila Model, Michael Mccarthy Aug 2013

Studying Aggregate Formation By Amyotrophic Lateral Sclerosis-Associated Mutant Sod1 Protein In Drosophila Model, Michael Mccarthy

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

A common pathological hallmark of most neurodegenerative disorders is the presence of protein aggregates in the brain. Understanding the regulation of aggregate formation is thus important for elucidating disease pathogenic mechanisms and finding effective preventive avenues and cures. Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a selective neurodegenerative disorder predominantly affecting motor neurons. The majority of ALS cases are sporadic, however, mutations in superoxide dismutase 1 (SOD1) are responsible for about 20% of familial ALS (fALS). Mutated SOD1 proteins are prone to misfold and form protein aggregates, thus representing a good candidate for studying aggregate ...


Neurodegeneration After Cardiac Arrest: Cell Death Mechanisms And Methods Of Neuroprotection, Michael Paine Jan 2013

Neurodegeneration After Cardiac Arrest: Cell Death Mechanisms And Methods Of Neuroprotection, Michael Paine

Publicly Accessible Penn Dissertations

Brain injury after cardiac arrest is a significant contributor to morbidity and mortality. Selectively vulnerable neuron populations undergo delayed neurodegeneration in the hours to days following reperfusion. Multiple factors influence neuronal death after global brain ischemia, including excitatory synaptic input, mitochondrial dysfunction, oxidative stress, inflammation, and disruption of intracellular Ca2+ homeostasis. In hippocampal CA1 pyramidal neurons, these factors activate cell death via pathologic activity of calpains, the family of Ca2+-dependent proteases, and calpain inhibition protects against neurodegeneration. Therefore, we hypothesized that pathologic calpain activity is necessary and sufficient for neurodegeneration in other selectively vulnerable neuron populations. In this thesis ...


Change And Impact Of Microrna Modification With Age In Drosophila Melanogaster, Masashi Abe Jan 2013

Change And Impact Of Microrna Modification With Age In Drosophila Melanogaster, Masashi Abe

Publicly Accessible Penn Dissertations

microRNAs (miRNAs) are 20~24nt small RNAs that are critical for many biological aspects, from development to age-associated processes. Starting from the identification of the first miRNA, lin-4, hundreds of miRNAs have been discovered across species. To reveal the role of miRNAs in aging, studies have profiled changes in miRNA levels with age. However, increasing evidence suggests that miRNAs show heterogeneity in length and sequence in different biological contexts. Despite the observation of such heterogeneity, it is largely unknown how such heterogeneity is generated, and whether it is biologically regulated or important. Here we report the characterization of a novel ...


Progress Towards Understanding Of Mechanisms Of Action Of Potent Multifunctional Disease Modifying Therapeutics For Parkinson's Disease & Investigating The Methamphetamine-Induced Striatal Microglia Activation., Mrudang M. Shah Jan 2013

Progress Towards Understanding Of Mechanisms Of Action Of Potent Multifunctional Disease Modifying Therapeutics For Parkinson's Disease & Investigating The Methamphetamine-Induced Striatal Microglia Activation., Mrudang M. Shah

Wayne State University Dissertations

PROGRESS TOWARDS UNDERSTANDING OF MECHANISMS OF ACTION OF POTENT MULTIFUNCTIONAL DISEASE MODIFYING

THERAPEUTICS FOR PARKINSON'S DISEASE.

by

MRUDANG MANOJKUMAR SHAH

December 2013

Advisor: Dr. Aloke Dutta

Major: Pharmaceutical Sciences

Degree: Doctor of Philosophy

Our long term goal is to design and develop potent multifunctional disease modifying therapeutics for Parkinson's disease. The objective of my dissertation was to understand the mechanisms of action of some potent small molecules (synthesized in our lab) as a disease modifying Parkinson's disease therapeutic. The objective was achieved by pursuing the following two specific aims:

1. Investigating anti-oxidant and neuroprotective effects of a ...


Endocrine Disrupting Compound 4-Nonylphenol And Neurodegeneration, Jessica Martinez Jurado Jan 2013

Endocrine Disrupting Compound 4-Nonylphenol And Neurodegeneration, Jessica Martinez Jurado

Open Access Theses & Dissertations

Neurodegeneration, a progressive loss of nerve cells (neurons), occurs in many neurological disorders including Alzheimer's disease, Parkinson's disease, Schizophrenia, and drug addiction. Cytoskeletal disruption in neurons and aggregation of proteins associated with these disorders is the hallmark of neurodegeneration. However, the cause of neurodegenerative disorders is unknown and currently there are no effective drug treatments. Aging is the most consistent risk factor for developing a neurodegenerative disorder, and recent evidence suggests that environmental factors, which act as endocrine disruptors, pose a risk in the disease process. 4- nonylphenol (4-NP), an endocrine-disrupting compound (EDC), has been shown to affect ...


Investigating Therapeutic Options For Lafora Disease Using Structural Biology And Translational Methods, Amanda R. Sherwood Jan 2013

Investigating Therapeutic Options For Lafora Disease Using Structural Biology And Translational Methods, Amanda R. Sherwood

Theses and Dissertations--Molecular and Cellular Biochemistry

Lafora disease (LD) is a rare yet invariably fatal form of epilepsy characterized by progressive degeneration of the central nervous and motor systems and accumulation of insoluble glucans within cells. LD results from mutation of either the phosphatase laforin, an enzyme that dephosphorylates cellular glycogen, or the E3 ubiquitin ligase malin, the binding partner of laforin. Currently, there are no therapeutic options for LD, or reported methods by which the specific activity of glucan phosphatases such as laforin can be easily measured. To facilitate our translational studies, we developed an assay with which the glucan phosphatase activity of laforin as ...


The Inflammatory Response Initiated By The Spleen To Ischemic Stroke, Hilary Seifert Jan 2013

The Inflammatory Response Initiated By The Spleen To Ischemic Stroke, Hilary Seifert

Graduate Theses and Dissertations

The peripheral immune system plays a role in delayed neural injury after stroke. This response originates from the spleen as splenectomy prior to middle cerebral artery occlusion (MCAO) in rats significantly reduces infarct volume in the brain. This research is based on the hypothesis that inhibiting the splenic response will reduce neurodegeneration after stroke. Studies in animals have implicated lymphocytes as the immune cell type that is detrimental following MCAO. Interferon gamma (IFNγ) has been identified as a pro-inflammatory cytokine that is also detrimental following stroke. IFNγ is important because it activates microglia and macrophages in a pro-inflammatory nature that ...


Roles Of Manganese And Protein Kinase Signaling In Cell Culture And Animal Models Of Prion Disease, Dustin Paul Martin Jan 2013

Roles Of Manganese And Protein Kinase Signaling In Cell Culture And Animal Models Of Prion Disease, Dustin Paul Martin

Graduate Theses and Dissertations

Despite several decades of dedicated research by a diverse array of researchers from around the globe, the molecular mechanisms underlying neuronal loss during transmissible spongiform encephalopathy (TSE) remain to be elucidated. Additionally, the etiology of so-called "sporadic" cases of TSE, which represents the vast majority of cases in both humans and animals, remains unknown. Several recent advancements in the understanding of other protein misfolding neurodegenerative disorders including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosi (ALS), and TSE have highlighted the similarities between disease etiopathogenesis which may broaden the diversity of potential future therapies. As our understanding ...


Proteolytic Processing Of The Amyloid Precursor Protein During Apoptosis And Cell Cycle: Implications For Alzheimer's Disease, Tina N. Fiorelli Jan 2013

Proteolytic Processing Of The Amyloid Precursor Protein During Apoptosis And Cell Cycle: Implications For Alzheimer's Disease, Tina N. Fiorelli

Graduate Theses and Dissertations

Alzheimer's disease is characterized by the presence of amyloid plaques, made up primarily of Aϐ peptides, and neurofibrillary tangles, containing hyperphosphorylated tau. Aϐ is generated by sequential proteolysis of the amyloid precursor protein (APP) by beta and gamma secretases. The leading hypothesis of Alzheimer's disease pathogenesis is the amyloid cascade hypothesis, which suggests that amyloid is central to the disease process. However, tau pathology correlates more closely with cognitive dysfunction and follows a predictable anatomical course through the brain. We hypothesize that if Aϐ is upstream of tau pathology and tau pathology follows this predictable course through the ...