Genetics and Genomics Commons^™

Screen For Beneficial Genetic And Chemical Modifiers In Drosophila Models Of Als And Traumatic Brain Injury, Will Bonderer

Biological Sciences Theses and Dissertations

The underlying molecular processes of aberrant protein expression in neurodegeneration are intricate and multifaceted, with ribosome-associated quality control (RQC) emerging as a promising avenue of exploration. Ribosome-associated quality control is integral to cellular function. Its evolutionarily conserved pathway encompasses a network of mechanisms designed to ensure the fidelity of protein synthesis, folding, and degradation within the cells of all eukaryotes. The ribosome, central to protein synthesis, plays a pivotal role in this quality control network, and its malfunction can lead to the accumulation of misfolded or aberrant proteins. In the context of neurodegenerative disorders, this dysfunction can have dire consequences. …

Methamphetamine-Induced Dna Double-Stranded Breaks: The Impact Of The Dopamine Transporter And Insights Into The Mechanisms Of Dna Damage In Mouse Neuro 2a Cells, Lizette Couto

Dissertations, Theses, and Capstone Projects

Methamphetamine (METH) abuse remains a global health concern, with emerging evidence highlighting its genotoxic potential. In the central nervous system METH enters dopaminergic cells primarily through the dopamine transporter (DAT), which controls the dynamics of dopamine (DA) neurotransmission by driving the reuptake of extracellular DA into the presynaptic neuronal cell. Additional effects of METH on the storage of DA in synaptic vesicles lead to the dysregulated cytosolic accumulation of DA. Previous studies have shown that after METH disrupts intracellular vesicular stores of DA, the excess DA in the cytosol is rapidly oxidized. This generates an abundance of reactive oxygen species …

Structural And Functional Consequences Of Pde6 Prenylation In Rod And Cone Photoreceptors, Faezeh Moakedi

Graduate Theses, Dissertations, and Problem Reports

Phosphodiesterase-6 (PDE6) serves as a pivotal component in the phototransduction pathways of both cone and rod photoreceptors. In cones, PDE6 consists of tetrameric subunits: inhibitory (γ') and catalytic (α'). The catalytic subunit, PDE6α', contains a C-terminal prenylation motif. Deletion of this motif is associated with achromatopsia (ACHM), a form of color blindness. The mechanisms underlying the disease and the roles of PDE6 lipidation in vision remain elusive. Meanwhile, rod PDE6 is composed of α and β catalytic subunits and γ inhibitory subunits, with alterations in the C-terminal "prenylation motif" of PDE6β linked to retinitis pigmentosa (RP) pathology. In this comprehensive …

Characterization Of Pathological Tau Mutants, Charles J. Mcdonald

Dissertations, Theses, and Capstone Projects

Tau is a protein expressed exclusively in glia and neurons in the central nervous system and implicated in several neurogenerative diseases called “tauopathies”. Among all the tauopathies, one third is characterized by the presence of genetic mutations leading to the synthesis of tau proteins with single amino acid substitutions at specific locations and affecting protein function. While most of the initial studies have emphasize the functional role of tau as modulator of the axonal cytoskeleton, it has recently been well accepted that tau is also an intrinsically disordered protein that tends to form membraneless organelles called coacervates, due to a …

Utilizing Crispr Cas9 To Visualize Dopamine Receptors In Caenorhabditis Elegans, Lauren Michelle Velasquez

Electronic Theses, Projects, and Dissertations

Dopamine (DA) is a neurotransmitter with imperative implications in many functions including movement, reward, and cognition. Studying the pathways of dopaminergic neurons at multiple levels allows us to understand the ways in which these systems can go wrong. We study dopamine in a model system such as the worm Caenorhabditis elegans because of its relatively simple and well-characterized nervous system. DA is involved in regulating chemosensory behaviors in worms. The purpose of this research project is to definitively answer the following question: Are the dopamine receptors DOP-1 and DOP-4 expressed in chemosensory neurons? Previous reporter assays show that neither of …

Validating A New In Vivo Model To Study Als, Izabela J. Cimachowska

Student Theses and Dissertations

Buildup of oxidative stress and mitochondrial dysfunction are well known characteristics of both sporadic and hereditary amyotrophic lateral sclerosis (ALS). While both forms of the disease seem to arise from common cellular dysfunction, the genetic disease is studied to a much greater extent. Engineering novel animal models of the sporadic form of the disease is crucial for development of druggable targets to treat ALS and understand the underlying mechanisms. Interestingly, accumulation of oxidative stress by exacerbated emission of reactive oxygen species (ROS) from presynaptic mitochondria is a hallmark of both hereditary and sporadic ALS. Previous work by our laboratory showed …

The Role Of Parkin In Mitochondrial Dna, Eliezer Lichter

Theses & Dissertations

Mitochondria are at the center of biological phenomena such as aging and diseases, especially neurodegenerative diseases. While the discovery of mitochondria only came approximately 200 years after the cell was discovered, a lot of progress has been made since. The mitochondrial genome encodes proteins vital for mitochondrial function. These proteins are only a subset of the proteins present in mitochondria; the rest are nuclear encoded. The nucleus also encodes cytosolic proteins vital for mitochondrial maintenance. One of these is Parkin, an E3 ubiquitin ligase that ubiquitinates mitochondrial proteins as mitochondria become depolarized. Its activity has been shown to be involved …

Med12 Is A Critical Regulator Of Neural Crest Lineage And Nervous System Myelination, Fatma Betul Aksoy Yasar

Dissertations & Theses (Open Access)

The Mediator complex (MED) is a multi-subunit protein complex integral to the eukaryotic transcription machinery. MED12 is a Cdk8- regulatory kinase module subunit directly implicated in human disease and is genetically altered in neurological disease and cancer. Numerous attempts at generating an in vivo system to study the role of Med12 failed due to embryonic lethality associated with germline or developmental disruption of Med12 gene. To understand the cellular and molecular processes associated with its role in disease, we generated multiple mouse models with targeted depletion of MED12 in distinct cellular lineages. Our genetically engineered models with induced and conditional …

Chemosensory Receptors In Berghia Stephanieae: Bioinformatics And Localization, Kelsi L. Watkins

Masters Theses

Chemosensation is achieved through the binding of chemical signals to chemoreceptor proteins embedded in the membranes of sensory neurons. The molecular identity of these receptors, as well as the downstream processing of chemosensory signals, has been well studied in arthropods and vertebrates. However, very little is known about molluscan chemosensation. The identity of chemoreceptor proteins in the nudibranch mollusc Berghia stephanieae are unknown. Data from other protostome and molluscan studies suggest Berghia may use ionotropic receptors for some forms of chemoreception. This study used a bioinformatics approach to identify potential chemosensory ionotropic receptors in the transcriptome of Berghia. A …

Novel Therapeutic Strategies For Alzheimer’S Disease: Prostaglandin D2 Signaling And Its Human Polymorphisms As Well As A Polypharmacological Approach, Charles H. Wallace

Dissertations, Theses, and Capstone Projects

Alzheimer’s disease (AD) is an age related neurodegenerative disease with pathology that includes amyloid plaques, neurofibrillary tangles and non-resolving neuroinflammation. Non-resolving neuroinflammation lasts the entire course of the disease and has deleterious effects and is often thought to accelerate AD pathology. Non-Steroidal Anti-inflammatory Drugs (NSAIDs) have commonly been used as therapeutics to treat pain, inflammation and vascular. NSAIDs work by altering the cyclooxygenase (COX) mediated biosynthesis of prostaglandins which are lipid mediators that have many physiological functions, for example nociception, inflammation and vasodilation. Epidemiological studies support the notion that NSAIDs could be used to treat AD. Yet, clinical trials using …

Genetic Determinants Of Primary Nociceptor Sensitivity In Drosophila Melanogaster, Christine Hale

Electronic Theses and Dissertations

Abnormal pain affects ~50 million adults nationwide. With many of the current treatment options for chronic pain, such as opioid analgesics, carrying side effects such as the threat for addiction, research into safer and more effective options for chronic pain relief is crucial. Abnormal alterations in nociceptive sensitivity, which is the sensitivity of peripheral sensory neurons that detect noxious stimuli, can underlie, and perpetuate chronic pain. However, much is still unknown about the mechanism of how these abnormal alterations in sensitivity occur. To help elucidate genetic components controlling nociceptive sensitivity, the Drosophila melanogaster larval nociception model has been used …

The Effects Of Physical Function And Genetics On Cognition And Blood Biomarkers In Individuals At-Risk For Alzheimer’S Disease And Related Dementias, Joshua Louis Gills

Graduate Theses and Dissertations

Alzheimer’s disease and related dementia (ADRD) rates are expected to triple by the year 2050. Early detection and specific mitigation efforts are warranted to blunt the alarming rate. Physical function (PF) declines with age, but higher physical function is associated with better cognitive functioning in middle-to- older age individuals. Moreover, greater physical activity (PA) is associated with better global cognition; however, Apoliporotein e4 carriers may not gain the same benefits with exercise. Additionally, plasma phosphorylated tau 217 (p-tau217) has been identified as a novel diagnostic ADRD biomarker which needs further research to examine associations with risk factors. Therefore, the aims …

The Effects Of Deletion Of The Cytoplasmic Domain Of Robo3 On Drosophila, Jessie Agcaoili

Biological Sciences Undergraduate Honors Theses

My research project examines how the deletion of the cytoplasmic domain affects the function of Robo3. If Robo3 is signaling repulsion in response to SLIT this activity should require the cytoplasmic domain. I investigated the functional importance of Robo3 by deleting the cytoplasmic domain of Robo3 using a CRISPR-based technique. This modified gene was then injected into Drosophila embryos where it replaced the normal copy of the gene. Embryos expressing the modified version of robo3 in place of normal robo3 were dissected and examined.

Alzheimer's Disease: A Comprehensive Review Including Personal Experience From Retirement Home Patients, Sydney Fox

Honors Theses

Alzheimer’s Disease is a neurodegenerative illness and disease, the most common type of dementia, and the sixth leading cause of death (Sá et al., 2012). The disease was discovered in 1906 and named after Dr. Alois Alzheimer, a psychiatrist and neuropathologist. Over time, a variety of hypotheses have developed regarding the cause behind this multifactorial disease, and these will be disclosed in a later section. Nonetheless, the disease was first observed in changes of the brain tissue of a woman who was said to have die from an unusual mental illness with many abnormal bumps. These bumps are now recognized …

Illuminating Transfer Rna Variants As Genetic Modifiers In Models Of Human Disease, Jeremy T. Lant

Electronic Thesis and Dissertation Repository

Transfer RNAs (tRNAs) physically link the genetic code to an amino acid sequence, by recruiting amino acids to three-nucleotide codons in messenger RNAs. To ensure that the genetic code is translated as intended, tRNAs must be accurately aminoacylated and faithfully recognize codons in the ribosome during protein synthesis. Given the critical function of tRNAs, it has often been assumed that mutations in human tRNA genes would be either lethal to cells or not significantly impair tRNA function. My goal was to rigorously test this assumption in mammalian cell models, prompted by the recent discovery of unprecedented variation in human tRNA …

The Neurobiological Underpinnings Of Depression-Related Maternal Behavior Deficits, Sarah B. Winokur

Doctoral Dissertations

Maternal caregiving is a dynamic process that requires extensive cognitive, motivational, and affective processing. World-wide, approximately 17% of mothers are diagnosed with postpartum depression yearly (Wang et al., 2021). Untreated, mothers with postpartum depression experience deficits in cognition, motivation, affect, and parenting (Arteche et al., 2011; Dix and Meunier, 2009; Lovejoy et al., 2000). Although postpartum depression is related to compromised parenting, to date, few studies have examined the neurobiological mechanisms by which maternal behavior is compromised in postpartum depression (Field, 2010; Murray et al., 1996)_. This dissertation aims to examine how depression neurobiologically disrupts parenting abilities. These studies …

Novel Strategies For Glutamate Clearance In The Glia-Deprived Synaptic Hub Of C. Elegans, Joyce Chan

Dissertations, Theses, and Capstone Projects

As the major excitatory neurotransmitter in the mammalian brain, Glutamate (Glu) is critical for normal neuronal physiology. Disruption in Glu clearance results in hyper-stimulation of glutamatergic circuits, potentially leading to excitotoxic neurodegeneration. The canonical model of brain connectivity describes glutamatergic synapses as well insulated and enveloped by glia. These glia express Glu Transporters (GluTs) which work to clear Glu following synaptic activity. However, critical areas of the brain such as the mammalian hippocampus display poor synaptic isolation, which may result in Glu spillover between adjacent synapses and subsequent loss of circuit specificity. How accurate signal transmission is achieved in these …

Examining Development And Function Of Pretectal Visual Neural Circuits In Gs Homeobox 1 Mutant Zebrafish, Alexandra Rose Schmidt

Graduate Theses, Dissertations, and Problem Reports

Brain development requires a coordinated genetic code to regulate initial cell identity determination, migration, and connectivity, to establish function of neural circuits. Independent neural circuits underlie our ability to produce both complex and innate behavioral responses to sensory stimuli that are often conserved across vertebrate organisms. Sensory processing disruptions are associated with several neurodevelopmental disorders (NDDs). Therefore, gene mutations altering neurodevelopment can lead to changes influencing structure and function of individual neural circuits, causing behavioral deviations in sensory responsiveness. Crucial gene networks that define functional properties of sensory domains are often explored using non-mammalian vertebrate models, such as the zebrafish. …

Deciphering The Role Of Hsp110 Chaperones In Diseases Of Protein Misfolding, Unekwu M. Yakubu

Dissertations & Theses (Open Access)

Molecular chaperones maintain protein homeostasis (proteostasis) by ensuring the proper folding of polypeptides. Loss of proteostasis has been linked to the onset of numerous neurodegenerative disorders including Alzheimer’s, Parkinson’s, and Huntington’s disease. Hsp110 is a member of the Hsp70 class of molecular chaperones and acts as a nucleotide exchange factor (NEF) for Hsp70, the preeminent Hsp70-family protein folding chaperone. Hsp110 promotes rapid cycling of ADP for ATP, allowing Hsp70 to properly fold nascent or unfolded polypeptides in iterative cycles. In addition to its NEF activity, Hsp110 possesses an Hsp70-like substrate binding domain (SBD) whose biological roles are undefined. Previous work …

Investigation Of Notch Signaling In Cone Fate Specification In Vertebrate Retina, Xueqing Chen

Dissertations, Theses, and Capstone Projects

In the vertebrate retina, cone photoreceptors are crucial for high acuity color vision. Several retinal diseases lead to loss of cones and there is a need to identify the normal developmental genesis of these cells to inform the development of stem cell-based therapies. Cone genesis has previously been shown to be repressed by Notch signaling, however, the mechanism by which Notch signaling controls cone fate determination is still unclear. It has been identified that cone photoreceptors are formed from multipotent retinal progenitor cells (RPCs) that first generate genetically-defined, restricted RPCs with limited mitotic and fate potential to preferentially form cones …

Having A High-Activity Catechol-O-Methyltransferase Allele Is Associated With Elevated Anxiety And Lower Salivary Dehydroepiandrosterone But Also Lower Alpha Amylase In Children With Chromosome 22q11.2 Deletion Syndrome., Jessie Beebe

University of New Orleans Theses and Dissertations

Chromosome 22q11.2 deletion syndrome (22q11.2DS) results from a hemizygous deletion located on the long arm of chromosome 22. The most common deletion sizes affect between 30 and 90 genes. Individuals with 22q11.2DS may develop serious developmental and psychiatric disorders. The phenotype is highly variable, however, and may be influenced by allelic variation of the retained copies of genes covered by the deletion. I set out to examine the effects of two genes, catechol-O-methyltransferase (COMT) and proline dehydrogenase (PRODH), in relation to anxiety in children and adolescents with 22q11.2DS. Individuals with the major COMT allele (higher activity) have significantly higher anxiety …

Mechanisms Of How Diet And Light Interact To Influence Drosophila Longevity Through The Eye, Charles H. Lau

Natural Sciences and Mathematics | Biological Sciences Master's Theses

Previous studies in Drosophila melanogaster have established that overexposure to light damages photoreceptors and that photoreceptor degeneration contributes to shortened lifespans. However, the role of diet and circadian rhythms in the eye has not yet been elucidated. Many vital processes in the eye are regulated by circadian rhythms, and circadian misalignment has been proven as a driver of aging. In the eye, one of the most enriched circadian functions is phototransduction. Phototransduction plays a major role in the organism’s ability to detect light. Our lab has previously proven that Dietary Restrictions (DR) can play a role in amplifying circadian rhythms …

Translational Fidelity And Its Role In Neuronal Homeostasis, Markus Terrey

Electronic Theses and Dissertations

The process of translation, which refers to decoding genetic information from mRNA to protein, is vital for all cellular function. Translational fidelity starts at the level of aminoacylation of transfer RNAs (tRNA). This reaction is catalyzed by aminoacyl tRNA synthetases where each amino acid is transferred to its corresponding cognate tRNA. Because tRNAs harbor the anticodon sequence to decodes a particular mRNA codon, the specific aminoacylation of the tRNA with a cognate amino acid establishes the rules of decoding genetic code into proteins. Aminoacylated tRNAs are then delivered to ribosomes, where ribosomes in a highly organized manner need to accurately …

Cloning And Functional Characterizations Of Circular Rnas From The Human Mapt Locus, Justin R. Welden

Theses and Dissertations--Molecular and Cellular Biochemistry

Under pathophysiological conditions, the microtubule protein tau (MAPT) forms neurofibrillary tangles that are the hallmark of sporadic Alzheimer’s disease as well as familial frontotemporal dementias linked to chromosome 17 (FTDP-17). In this work, I report that MAPT forms circular RNAs through backsplicing of exon 12 to either exon 10 or exon 7 (12→10; 12→7), and that these circular RNAs are translated into proteins.

Using stable cell lines overexpressing the circular tau RNAs 12→7 and 12→10, we have discovered that the tau circular RNA 12→7 is translated in a rolling circle, giving rise to multiple proteins. This circular RNA …

The Receptor Basis Of Serotonergic Modulation In An Olfactory Network, Tyler Ryan Sizemore

Graduate Theses, Dissertations, and Problem Reports

Neuromodulation is a nearly ubiquitous process that endows the nervous system with the capacity to alter neural function at every level (synaptic, circuit, network, etc.) without necessarily adding new neurons. Through the actions of neuromodulators, the existing neural circuitry can be adaptively tuned to achieve flexible network output and similarly dynamic behavioral output. However, despite their near ubiquity in all sensory modalities, the mechanisms underlying neuromodulation of sensory processing remain poorly understood. In this dissertation, I address three main questions regarding the mechanisms of one modulator (serotonin) within one sensory modality (olfaction). I begin by establishing a "functional atlas" of …

Estrogen Disruption Of Hypothalamic Neural Activity, Princess Dickson

Cal Poly Humboldt theses and projects

The brain is highly dependent on the endocrine system for proper neurodevelopment, as it plays a key role in many biological processes. Bisphenol A is a chemical found in plastics that has the potential to mimic the effects of Estrogen in the body, at least weakly. People interact with plastic that contains BPA regularly, and people are at risk for exposure even before being born. The abundance of BPA, along with other exogenous estrogens, makes examining the relationship between early exposure and changes in brain activity imperative. The current study aims to establish a relationship between disrupted estrogen function and …

Employing High Probability Gene Choice Elements To Understand Singular Odorant Receptor Expression, Raena Mina

Dissertations, Theses, and Capstone Projects

The ability to detect odorous chemicals in the environment is the oldest of the senses necessary for survival, from escaping danger, finding mates, to locating food. It is said that humans can identify and discriminate up to a trillion different odor mixtures. For chemoreception to have such a high discriminatory power, would require a diverse population of cells dedicated for odor detection. These detector cells are the olfactory sensory neurons (OSNs), which express odorant receptors (ORs) that bind to chemical odors in the environment. In order to increase specificity and sensitivity, an essential property in olfaction is for each OSN …

Sleep Modifications In A Drosophila Melanogaster Model Of Fragile X Syndrome, Morgan Mclaughlin

Undergraduate Honors Theses

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disabilities, disruptions in sleep, and autism in humans. Mutations in Fragile X Mental Retardation gene 1 (FMR1), which codes for a protein that modifies the expression of many target proteins, are primarily responsible for this disorder. Genetic modifications of FMR1 can increase or decrease the overall amount of sleep in humans. A potential pharmaceutical target of FXS is dopamine, a critical neurotransmitter in the regulation of sleep and wakefulness. In fruit flies (Drosophila melanogaster) dopamine has been shown to alter sleep. The mushroom body, a structure in …

Do Innexins Function In The Extreme Cold Response Of Drosophila Melanogaster, Madison A. Ward

Masters Theses, 2020-current

Nociception is an organism’s ability to detect, process and reflexively respond to potentially damaging stimuli. While the process of nociception has clear, protective advantages, inappropriate and prolonged signaling can lead to chronic pain in humans. Nociception is a vital and genetically conserved process, thus cold nociception in Drosophilaprovides a model for identifying molecular components required for nociceptor function in vertebrates. Drosophila Class III dendritic arborization (da) neurons have previously been shown to be involved in the cold nociceptive response. Due to the importance of fast response to damaging stimuli, we hypothesize that electrical synapses are involved in cold nociception. …

Mushroom Body-Specific Gene Regulation By The Swi/Snf Chromatin Remodeling Complex, Kevin Cj Nixon

Electronic Thesis and Dissertation Repository

Over the lifetime of an organism, neurons must establish, remodel, and maintain precise connections in order to form neural circuits that are required for proper nervous system functioning. Disruptions in these processes can lead to neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorder. Mutations in genes encoding subunits of the SWI/SNF chromatin remodeling complex have been implicated in ID, yet the role of this complex in neurons is poorly understood. In this project, I established cell-type specific methods to examine the effect of SWI/SNF subunit knockdowns on gene transcription and chromatin structure in the memory-forming neurons of …