Molecular and Cellular Neuroscience Commons^™

Calcium Dyshomeostasis In Neurodegeneration, Nicholas Emanuel Karagas

Dissertations & Theses (Open Access)

Neurodegenerative diseases, despite constituting a major and growing cause of mortality globally, have few effective treatments. In order to develop novel therapeutics to combat neurodegeneration, a better understanding of the molecular mechanisms underlying these diseases is needed. Neurons rely on Ca²⁺ to mediate many of their unique functions, and aberrant Ca²⁺ signaling has been broadly implicated in neurodegeneration. The goal of this dissertation is to delineate specific examples of Ca²⁺ dyshomeostasis that I have uncovered in Drosophila models of neurodegeneration.

I first define the role a neurodegeneration-associated mutation plays in perturbing presynaptic [Ca²⁺], which is …

Dnajc7, A Molecular Chaperone Protein That Modulates Protein Misfolding In Amyotrophic Lateral Sclerosis (Als), Meaghan Kathleen Stoltz

Electronic Thesis and Dissertation Repository

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease associated with protein misfolding and dysregulated cellular protein quality control mechanisms. Molecular chaperones, and heat shock proteins (Hsp), are key players in maintaining cellular protein quality control. DNAJC7 is an understudied cytosolic Hsp40 that works together with Hsp70 and Hsp90 to regulate proper protein folding or degradation. Of note, mutations in the gene encoding DNAJC7 were discovered to cause familial ALS. We asked whether ALS-associated mutations in DNAJC7 compromise its function as a chaperone, which may cause the toxic accumulation of misfolded proteins. This study attempts to uncover the functions of DNAJC7 …

The Role Of The Leucine-Rich (Leur) Domain Of Rho Guanine Nucleotide Exchange Factor (Rgnef) In The Regulation Of Amyotrophic Lateral Sclerosis (Als) Associated Protein Tar Dna-Binding Protein Of 43 Kda (Tdp-43), Hind Amzil

Electronic Thesis and Dissertation Repository

The presence of neuronal cytoplasmic inclusions (NCIs) composed of RNA-binding proteins (RBPs) and neurofilaments is considered to be ALS’s neuropathological hallmark. RGNEF has been previously shown to interact with TDP-43 and to have a regulatory effect on the expression levels of NEFL mRNA and NFL protein in vitro. Here, I examined the mechanism of the RGNEF N-terminus, leucine-rich domain (LeuR) domain’s interaction with TDP-43. I observed that the minimal domain required is 110 amino acids (LeuR110), that the Ankyrin domain adjacent to LeuR110 does not participate, and that LeuR110 forms of a high molecular weight complex with TDP-43 in …

Differential Expression Of Rna In The Rat Peripheral Nervous System Following Nerve Injury And Treatment With Pain-Relieving Celecoxib-Loaded Nanomedicine, Andrea Stevens

Electronic Theses and Dissertations

The neuroinflammatory response to peripheral nerve injury is associated with chronic pain and significant changes in the expression profiles of RNAs in neurons, glia and infiltrating immune cells: a neuro-immune triad. Chronic constriction injury (CCI) of the rat sciatic nerve provides an opportunity to mimic neuropathic injury and quantitatively assess behavior and differential gene expression in individual animals. Macrophages that phagocytose intravenously injected nanoemulsion carrying the non-steroidal anti-inflammatory, NSAID, Celecoxib, naturally accumulate at the site of injury resulting in relief of CCI behavioral hyper-sensitivity. It is not known beyond the inhibition of cyclooxygenase-2 (COX-2) activity and the reduction in prostaglandin …

Effect Of S100b Deletion On Membrane Properties And Localization Of Ncald And Hpca, Natasha Hesketh

Graduate School of Biomedical Sciences Theses and Dissertations

Calcium signaling is particularly important for neuronal function. Neurons utilize a wide range of calcium-binding proteins. Dysregulation of such proteins is linked to neurodegeneration. Neurocalcin delta (NCALD), hippocalcin (HPCA), and S100B are calcium sensors that are expressed in the hippocampus, a brain region essential to memory and severely damaged in Alzheimer’s disease (AD). Despite the potential importance of these proteins, we do not fully understand the physiological significance of their relationship. Because NCALD and HPCA are known to interact with S100B, we hypothesized that the loss of S100B affects NCALD and HPCA localization, and therefore electrical properties, of hippocampal neurons. …

Elevated Cochlear Adenosine Causes Hearing Loss Via Adora2b Signaling, Jeanne Manalo

Dissertations & Theses (Open Access)

Over 538 million people in the world have been diagnosed with hearing loss (HL). Current treatments for the most common type of HL, sensorineural HL, are limited to hearing aids and cochlear implants with no FDA-drugs available. The hearing process demands an abundance of ATP and HL is often attributed to a disruption in this metabolic energy currency. Patients who lack adenosine deaminase (ADA), the enzyme that irreversibly metabolizes adenosine, have high levels of adenosine that yield severe health problems, including HL; however, the pathogenic mechanisms behind HL and adenosine remain elusive. Our lab has found a HL phenotype in …

Modulating Matrix Metalloproteases And Inflammation In Huntington’S Disease, Alejandro Lopez Ramirez

Natural Sciences and Mathematics | Biological Sciences Master's Theses

Huntington’s disease (HD) is a rare and incurable autosomal neurodegenerative disease affecting 1-10 in every 100,000 people in the world. There is no cure for HD and treatments available alleviate certain symptoms for short periods of time. Evidence suggests that neuropathology of HD begins with the proteolysis of the mutated Huntingtin (mHTT) protein. A variety of proteases, like the matrix metalloproteases, cleave mHTT creating proteinaceous fragments that are thought to be neurotoxic. As these fragments increase in the brain, the damage to neurons also increases, leading to chronic inflammation due to hyper reactive microglia and astrocytes attempting to minimize and …

Elucidation Of The Mechanisms By Which Anesthetics Induce Blood-Brain Barrier Breakdown And Delirium In The Elderly, George A. Godsey Ii

Graduate School of Biomedical Sciences Theses and Dissertations

Delirium is a highly prevalent neuropsychiatric or neurocognitive disorder that presents a major problem to modern healthcare. Patients suffering from delirium normally have a worse prognosis, prolonged hospital stay, increased hospital cost, long-term cognitive impairment, and higher mortality rates. Many factors can predispose one to develop delirium, which makes treating this disorder a daunting task. Unfortunately, delirium is the most common psychiatric syndrome found in the hospital setting. In fact, a form of delirium known as postoperative delirium (POD) is one of the most common postoperative complications faced by elderly patients undergoing surgery.

POD is a major problem in modern …

Targeting The Nt17 Of The Huntingtin Protein Via Natural And Chemical Modifications: Impact On Aggregation And Membrane Interactions, Faezeh Sedighi

Graduate Theses, Dissertations, and Problem Reports

Huntington Disease (HD) is a fatal neurodegenerative disorder caused by an expanded polyglutamine domain (polyQ) in the first exon of the huntingtin protein (htt-exon1). The major hallmark of HD is the accumulation of aggregates into proteinaceous inclusion bodies. PolyQ expansion in huntingtin promotes self-assembly into a variety of toxic aggregates such as oligomers, fibrils, and amorphous aggregates. The resulting heterogeneous mixture of distinct species makes it difficult to assign a toxic function to specific aggregate structures. In addition, htt interacts with a variety of membranous surfaces. The first 17 amino acids (Nt17) of htt directly flanking the polyQ domain functions …

Factors Influencing Huntingtin Aggregation At Surfaces: Implications For Huntington’S Disease, Sharon E. Groover

Graduate Theses, Dissertations, and Problem Reports

Huntington’s Disease (HD) is a genetic, neurodegenerative disease characterized by an abnormal polyglutamine (polyQ) expansion in the first exon of the huntingtin protein (htt). The polyQ domain facilitates aggregation and initiates the formation of a diverse collection of aggregate species, including fibrils, oligomers and annular aggregates. The first 17 amino acids of htt (Nt17) directly flank the polyQ domain and is a key factor in htt’s association to membranous structures. In addition to Nt17 being an amphipathic αhelix, it also promotes aggregation through self-association and contains numerous posttranslational modifications (PTMs) that can modulate toxicity and subcellular localization. For in depth …

Non-Invasive Method For Leptin Supplementation In Zebrafish (Danio Rerio), Regan Mcnamara

Williams Honors College, Honors Research Projects

I tested the hypothesis that recombinant leptin protein can be introduced to zebrafish in vivo through non-invasive soaking in a solution containing the protein. One way to study various molecules’ effects in vivo is through intraperitoneal or intracerebroventricular injections during the embryonic or larval stage, which is invasive, difficult to administer, and can have a high mortality rate. 48 hours post fertilization (hpf) zebrafish were soaked in a His-tagged recombinant leptin protein solution at 10 nM and 100 nM concentrations (produced by Genscript). After soaking, zebrafish larvae were washed extensively to remove all recombinant protein on their exterior before homogenization. …

Novel Post-Translational Modification And Function Of Fus: The Relevance To Amyotrophic Lateral Sclerosis, Alexandra Arenas

Theses and Dissertations--Toxicology and Cancer Biology

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the preferential death of motor neurons. Approximately 10% of ALS cases are familial and 90% are sporadic. Fused in Sarcoma (FUS) is a ubiquitously expressed RNA binding protein implicated in familial ALS and frontotemporal dementia (FTD). FUS is ubiquitously expressed in cells and has a variety of functions in the nucleus and cytoplasm. FUS mutations in the nuclear localization sequence (NLS) causes mislocalization of FUS in the cytoplasm, where it can undergo liquid-liquid phase separation and become stress granules or protein inclusions. Although FUS inclusion bodies can be found in …