Molecular Biology Commons^™

The Rpm-1/Phr Signaling Hub Modulates Tau-Induced Neurodegeneration Through Regulation Of Microtubule Stability And Mapk Pathways In C. Elegans, Xinxing Ding

Theses and Dissertations

Neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia, are characterized by the accumulation of pathological tau proteins and progressive neuronal loss. Although research regarding tau-mediated toxicity is extensive, the specific pathology that determine whether neurons maintain homeostasis or succumb to collapse under tau-induced stress remain incompletely elucidated. A central, yet still insufficiently understood, feature of these diseases is the disruption of the microtubule (MT) cytoskeleton . The PHR protein family is evolutionarily highly conserved; within this family, RPM-1 in C. elegans functions as an intracellular signaling hub that regulates axon development, synapse formation, axon termination, and various microtubule-associated processes. This …

The Neuroprotective Effect Of Cdc42 Inhibition In The G93a Mutant Hsod1 Mouse Model Of Als, Andrea Koly

Undergraduate Theses, Capstones, and Recitals

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by the selective loss of upper and lower motor neurons, leading to muscle weakness, neuromuscular junction (NMJ) degeneration, paralysis, and eventual death due to respiratory failure. Despite extensive research, effective disease-modifying therapies remain limited, underscoring the need to identify novel molecular targets involved in ALS pathogenesis. Dysregulation of Rho family GTPases has been implicated in neurodegeneration, with Rac and Rho exerting opposing effects on neuronal survival; however, the role of the closely related GTPase Cdc42 remains poorly understood in ALS. In this study, the therapeutic potential of inhibiting …

The Pam-1 Aminopeptidase Does Not Protect Against Ptl-1 Mediated Neurodegeneration In C. Elegans., Ethan E. Schuff

Honors College Theses

Debilitating neurodegenerative conditions are increasingly prevalent in our aging population, yet treatment options remain limited. Though neurodegenerative diseases vary in pathophysiology and clinical manifestations, these diseases are related to one another in that many involve misfolded proteins. Tau is a member of the microtubule-stabilizing MAPT/MAP2/MAP4 family, and misfolded tau proteins form the neurotoxic aggregates called neurofibrillary tangles (NFTs) found in the brains of patients with Alzheimer's disease and other neurodegenerative diseases. Designing a study to elucidate the neurotoxic role of tau is difficult because other MAPs may have compensatory mechanisms which confound study data. Caenorhabditis elegans (C. elegans) …

Disrupted Nuclear Function And Nucleocytoplasmic Transport In Parkinson’S Disease, Ichiro M. Matoba

The Cardinal Edge

No abstract provided.

Investigating The Effects Of Nucleopore Defects On The Cellular Response To Stress In Als/Ftd Ipsc-Derived Neurons, Alicia Christine Collins

Open Access Dissertations

Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) is a progressive neurodegenerative disease spectrum characterized by motor dysfunction, cognitive decline, and death within a few years of clinical onset. Hallmark features of ALS/FTD include defects in nucleocytoplasmic transport (NCT) and abnormal cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43, both of which have been shown to be exasperated by oxidative stress (OS). It remains unclear how these processes are connected and how they collectively contribute to neurodegeneration. To fill this gap of knowledge, we used human embryonic kidney cells, neuroblastoma cells, and induced pluripotent stem cell-derived cortical neurons harboring the ALS/FTD C9ORF72 …

Tdp43 Autoregulation Gives Rise To Dominant Negative Isoforms That Are Tightly Controlled By Transcriptional And Post-Translational Mechanisms, Megan M. Dykstra, Kaitlin Weskamp, Nicolás B. Gómez, Jacob Waksmacki, Elizabeth Tank, M. Rebecca Glineburg, Allison Snyder, Emile Pinarbasi, Michael Bekier, Xingli Li, Morgan R. Miller, Jen Bai, Shameena Shahzad, Neha Nedumaran, Clare Wieland, Corey Stewart, Sydney Willey, Nikolas Grotewold, Jonathon Mcbride, John J. Moran, Aditya V. Suryakumar, Michael Lucas, Peter M. Tessier, Michael Ward, Peter K. Todd, Sami J. Barmada

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal TDP43 isoforms that are predominantly cytosolic in localization, prone to aggregation, and enriched in susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 isoforms are difficult to detect in comparison to full-length (fl)TDP43, raising questions regarding their origin and selective regulation. Here, we show that sTDP43 is created as a by-product of TDP43 autoregulation and cleared by nonsense-mediated RNA decay (NMD). sTDP43-encoding transcripts that escape NMD are rapidly degraded post-translationally via the proteasome …

Investigating The Role Of Fnci-1 In The Development And Function Of The C. Elegans Nervous System, Meagan Collins

Open Access Master's Theses

Fanconi Anemia (FA) is a rare human genetic disease caused by mutation of any of twenty-three genes on the FA pathway, which functions in the repair of DNA damage and the maintenance of genome stability. FA is clinically characterized by congenital abnormalities and a predisposition to aplastic anemia and malignancies. Recently, progressive neurological symptoms and abnormal neurological findings on imaging have been noted in FA patients, including cerebral and cerebellar lesions, calcification, necrosis, gliosis, and associated acute and chronic neurological symptoms; this constellation of symptoms has been termed Fanconi Anemia-Associated Neurological Syndrome (FANS).

To elucidate the molecular etiology of FANS, …

Therapeutic Potential Of Astrocyte-Derived Extracellular Vesicles In Mitigating Cytotoxicity And Transcriptome Changes In Human Brain Endothelial Cells, Ruth Juliana Stewart

Doctoral Dissertations

Extracellular vesicles (EVs) play a major role in cell-to-cell communication via the horizontal transfer of RNA, DNA, proteins, and lipids that affect the physiological response of the recipient cells. Astrocytes are a type of glial cell that exerts a protective effect on neurons and brain endothelial cells. The astrocytes and the endothelial cells form the blood-brain barrier. Due to their nano-size and non-complex structure, EVs can efficiently cross the blood-brain barrier. This study investigated and assessed the impact of EVs on reducing oxidative DNA damage in human brain endothelial cells (HBECs). The protective potential of astrocyte-derived EVs was determined by …

Roles Of Mitochondrial Chchd2 And Gpcr-Associated Β-Arrestin2 In The Pathogenesis Of Lewy Body Disorders, Teresa R. Kee

USF Tampa Graduate Theses and Dissertations

Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) is a mitochondrial protein that plays important roles in cristae structure, oxidative phosphorylation, and apoptosis. Multiple mutations in CHCHD2 have been associated with Lewy body disorders (LBDs), such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), with the CHCHD2T61I mutation being the most widely studied. We generated the first transgenic mouse models expressing human CHCHD2WT and the PD-linked CHCHD2T61I mutation driven by the mPrP promoter. CHCHD2T61I Tg, but not CHCHD2WT Tg mice exhibit perinuclear mitochondrial aggregates, neuroinflammation, and have impaired long-term synaptic plasticity associated with synaptic dysfunction. Dopaminergic neurodegeneration, a hallmark of PD, …

Blocking The Dimerization Of Polyglutamine-Expanded Androgen Receptor Protects Cells From Dht-Induced Toxicity By Increasing Ar Turnover, Allison Lisberg, Yuhong Liu, Diane E. Merry

Department of Biochemistry and Molecular Biology Faculty Papers

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular degenerative disease caused by a polyglutamine expansion in the androgen receptor (AR). This mutation causes AR to misfold and aggregate, contributing to toxicity in and degeneration of motor neurons and skeletal muscle. There is currently no effective treatment or cure for this disease. The role of an interdomain interaction between the amino- and carboxyl-termini of AR, termed the N/C interaction, has been previously identified as a component of androgen receptor-induced toxicity in cell and mouse models of SBMA. However, the mechanism by which this interaction contributes to disease pathology is unclear. …

Evaluation Of Rotenone Mediated Α-Synuclein Spreading And Neurotoxicity In Intra-Striatal Injection Of Α-Synuclein Pff Model Of Parkinson’S Disease, Engila Khan

Theses

In the last 25 years, the prevalence of Parkinson’s Disease (PD) across the globe has doubled. Clinical manifestations of this progressive neurodegenerative disorder include motor symptoms such as tremors, bradykinesia, postural instability, etc., which occur due to selective loss of dopaminergic neurons in the Substantia nigra (SNC) in the brain. The histopathological feature of PD is the presence of intra-neuronal aggregates of proteins called Lewy bodies, a major constituent of which is α-synuclein (α-syn).

Epidemiological studies to date have reported a connection between exposure to environmental neurotoxins such as Rotenone (a mitochondrial complex 1 inhibitor) and increased risk of PD …

Probing Amyloid-Beta Protein Structure And Dynamics With A Selective Antibody, Shikha Grover

Dissertations

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. The AD brain is characterized by significant neuronal loss and accumulation of insoluble fibrillar amyloid-β protein (Aβ) plaques and tau protein neurofibrillary tangles in the brain. However, over the last decade, many studies have shown that the neurodegenerative effect of Aβ may in fact be caused by various soluble oligomeric forms as opposed to the insoluble fibrils. Furthermore, the data suggest that a pre-fibrillar aggregated form, termed protofibrils, mediates direct neurotoxicity, and triggers a robust neuroinflammatory response.

Antibodies targeting the various conformation of Aβ are important therapeutic agents to prevent the progression …

Transcriptional Mechanisms Of Neuroprotection In Excitotoxicity Driven Neurodegeneration In C. Elegans, Zelda Z. Mendelowitz

Dissertations, Theses, and Capstone Projects

Excitotoxicity is notorious for triggering neuronal cell death in both developmental and adult-onset neurodegenerative diseases. In excitotoxicity, excessive concentrations of Glutamate in the synapse overstimulate Glutamate Receptors (GluRs) on postsynaptic neurons. While GluR mediated degenerative mechanisms remain obscure, GluR activation was surprisingly found to also have a neuroprotective effect through activation of specific transcriptional programs. To identify evolutionarily conserved transcriptional programs in neuroprotection we use a C. elegans model of excitotoxic necrosis (glt-3;nuIs5). We have identified that non-canonical activation of the transcription factor CRH-1/CREB mediates neuroprotection in our excitotoxicity model. We found the Histone Acetyl Transferase, MYS-1/KAT6, and the neuronal …

Modeling Developmental, Molecular, And Behavioral Effects Of An Apolipoprotein-E4 Fragment On The Embryogenesis Of Zebrafish, Madyson Mccarthy

Boise State University Theses and Dissertations

Although the increased risk of developing sporadic Alzheimer’s disease (AD) associated with the inheritance of the apolipoprotein E4 (APOE4) allele is well characterized, the molecular underpinnings of how ApoE4 imparts risk remains unknown. Enhanced proteolysis of the ApoE4 protein with a toxic-gain of function has been suggested and a 17 kDa amino-terminal ApoE4 fragment (nApoE4_1-151) has been identified in post-mortem human AD frontal cortex sections. Recently, we demonstrated in vitro, exogenous treatment of nApoE4_1-151 in BV2 microglial cells leads to uptake, trafficking to the nucleus and increased expression of genes associated with cell toxicity …

Impact Of Arginine Metabolism And Sensing In Mouse Models Of Alzheimer’S Disease, Chao Ma

USF Tampa Graduate Theses and Dissertations

Alzheimer’s disease (AD) remains the most common neurodegenerative disease in the central nervous system (CNS), with amyloidosis and tauopathy as their two main hallmarks. Typical AD pathologies include cerebral plaques deposited by amyloid-β, neurofibrillary tangles aggregated by tau, and neuroinflammation caused by activated brain myeloid cells. A critical theme is centered on impaired brain metabolism. Emerging evidence showed that impaired arginine metabolism was a novel biomarker pathway for AD. The manipulation of arginine metabolism by a critical enzyme arginase 1 (ARG1) in neurons indicated therapeutic benefits in alleviating tau pathology. Balanced cellular proteostasis was governed by the mechanistic target of …

The Importance Of Protein Context In Spinocerebellar Ataxia Type 3, Sean Luis Johnson

Wayne State University Dissertations

Spinocerebellar Ataxia Type 3 (SCA3) is a member of the family of polyglutamine (polyQ) neurodegenerative disorders that includes Huntington's Disease and several other SCAs. SCA3, the most common dominant ataxia in the world, is caused by polyQ tract expansion in the protein, ataxin-3. How SCA3 occurs and how to treat it remain unresolved issues. The primary culprit of toxicity in all polyQ diseases is the glutamine repeat: its abnormal expansion leads to neuronal dysfunction and death. With that said, there is indisputable evidence that the way polyQ-dependent toxicity presents—areas impacted, cellular processes perturbed—is predicated in large part on regions outside …

Granulins In Norm And Neurodegenerative Pathologies, Anukool Bhopatkar

Dissertations

Granulins (GRNs) are small, cysteine-rich modules produced from the proteolytic cleavage of the precursor protein called progranulin (PGRN). GRNs are present in the form of seven tandem repeats within the precursor and are known to be produced in the extracellular and in lysosomal environments. In physiology, PGRN and GRNs plays pleiotropic roles such as neuronal growth and differentiation, immunomodulation, wound healing. Recent studies have implicated pathological role for PGRN in Alzheimer disease (AD) and frontotemporal dementia (FTD) but specific mechanism(s) remains unclear. However, potential interactions between GRNs and Ab42 and TDP-43 seem like a plausible underlying mechanism. Studies presented here …

Determining The Role Of Methylglyoxal (Mgo) And The Trpa1 Channel In Inducing Astrocyte Senescence And Neurodegeneration, Natalie Hill

Natural Sciences and Mathematics | Biological Sciences Master's Theses

Aging is the largest risk factor for the development of Alzheimer’s disease (AD) and related dementias. A recently proposed driver of age-related pathologies is cellular senescence, a phenotype that consists of cell-cycle arrest and an inflammatory response known as the senescence-associated secretory phenotype (SASP). Although there is a link between the accumulation of senescent cells and neurodegeneration, much remains unknown about how senescent cells arise in the brain. Astrocytes are the most abundant cell type in the brain that serve important roles like supporting neurons and proliferating in response to stress. Methylglyoxal (MGO) is a glycolytic byproduct that can react …

Calcium Dyshomeostasis In Neurodegeneration, Nicholas Emanuel Karagas

Dissertations and 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 …

Tdp-43 Mediated Blood-Brain Barrier Permeability And Leukocyte Infiltration Promote Neurodegeneration In A Low-Grade Systemic Inflammation Mouse Model, Frank Zamudio, Anjanet R. Loon, Shayna Smeltzer, Khawla Benyamine, Nanda K. Navalpur Shanmugam, Nicholas J. F. Stewart, Daniel C. Lee, Kevin Nash, Maj-Linda B. Selenica

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Neuronal cytoplasmic inclusions containing TAR DNA-binding protein 43 (TDP-43) are a neuropathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's Disease (AD). Emerging evidence also indicates that systemic inflammation may be a contributor to the pathology progression of these neurodegenerative diseases.

METHODS: To investigate the role of systemic inflammation in the progression of neuronal TDP-43 pathology, AAV9 particles driven by the UCHL1 promoter were delivered to the frontal cortex of wild-type aged mice via intracranial injections to overexpress TDP-43 or green fluorescent protein (GFP) in corticospinal motor neurons. Animals were then subjected …

Alzheimer's And Amyloid Beta: Amyloidogenicity And Tauopathy Via Dyshomeostatic Interactions Of Amyloid Beta, Jordan Tillinghast

Senior Honors Theses

This paper reviews functions of Amyloid-β (Aβ) in healthy individuals compared to the consequences of aberrant Aβ in Alzheimer’s disease (AD). As extraneuronal Aβ accumulation and plaque formation are characteristics of AD, it is reasonable to infer a pivotal role for Aβ in AD pathogenesis. Establishing progress of the disease as well as the mechanism of neurodegeneration from AD have proven difficult (Selkoe, 1994). This thesis provides evidence suggesting the pathogenesis of AD is due to dysfunctional neuronal processes involving Aβ’s synaptic malfunction, abnormal interaction with tau, and disruption of neuronal homeostasis. Significant evidence demonstrates that AD symptoms are partially …

Investigating Autophagy Dysfunction Induced By A Parkinson's Disease-Causing Mutation In Vps35, Abir Ashfakur Rahman

Boise State University Theses and Dissertations

Parkinson’s Disease (PD) is an idiopathic disorder with no known cure. With number of cases steadily rising around the world, it is imperative to turn to the underlying cellular and molecular mechanisms of the disease manifestation and neurodegeneration to craft novel modes of therapy. VPS35 is one of the few genes that have identified and definitively linked to familial PD. The particular mutation that has been associated is known to cause dysfunction of a key cellular process known as autophagy. This process is primarily responsible for clearance of unwanted, damaged or misfolded proteins, among other things. Our study reveals an …

Cyclophilin 40 As A Novel Disaggregase, Jeremy Dustin Baker

USF Tampa Graduate Theses and Dissertations

The negative health and economic impacts of neurodegenerative diseases on Americans is astounding and accelerating with an aging population. The Alzheimer’s Association reports that 5.7 million Americans suffer from Alzheimer’s disease (AD), a number which is expected to increase to 14 million by 2050. In economic terms, AD and other neurodegenerative disorders will cost the US over $275 billion in 2018, rising to over $1 trillion annually by 2050. AD causes gross brain atrophy and is most damaging throughout the cortex and the hippocampus, regions required for higher cognitive function and memory. AD presents as tangles within neurons composed of …

Analysis Of The Secondary Neurodegenerative Consequences Of Primary Oligodendrocyte Stress Through The Use Of The Novel Obiden Mouse Model, Daniel Zdzislaw Radecki

Wayne State University Dissertations

The work of this project was to develop, test and characterize a potential novel mouse model of the neurodegenerative disease Multiple Sclerosis (MS). Historically, MS has been identified as a primary autoimmune disease of the central nervous system (CNS). However, treatments based on this view have met with limited success, and in most cases, fail to prevent progression of MS from mild to moderate and severe forms. Original observations regarding axonal and neuronal pathology in the white and gray matter of the CNS were rediscovered in the 1990s. These observations indicated that even in the absence of the immune system, …

Mitogen And Morphogen Signaling Dysregulation: Pathophysiological Influence In Pancreatic Cancer And Alzheimer’S Disease, Eric Cruz

Theses & Dissertations

Although the etiology of a particular disease will vary, there are genetic and epigenetic bottlenecks that frequently converge resulting in dysregulation of mitogenic and morphogenetic signaling. This propensity is acutely experienced in malignancy and neurodegenerative disease.

Here, we have first investigated the role of dysregulated signaling in the context of pancreatic cancer (PC). Morphogenetic signaling has been regarded as a pleiotropic pathway with the potential to promote and inhibit metastatic features. Our investigation of bone morphogenetic protein 2 (BMP-2), an archetypical member of the BMP superfamily, has revealed the presence of extracellular, intracellular, and long non-coding RNA products. Our findings …

The Role Of Daf-19 In Non-Ciliated Neurons: How Is Neural Development Regulated By Different Daf-19 Isoforms?, Zabdiel Ek Vazquez

Lawrence University Honors Projects

A degenerative disease-like phenotype, specifically reduction in synaptic protein levels in adult worms, is correlated with loss-of-function of the only RFX transcription factor gene, daf-19, in C. elegans. This gene encodes four known transcription factor isoforms, two of which are correlated with particular functions. The DAF-19C isoform activates genes responsible for cilia development, while DAF-19M is needed for cilia specification in males. A comparison of the transcriptome of daf-19 null and isogenic wild type adult worms suggests both positive and negative regulation of gene expression is correlated with the presence of DAF-19 proteins. We have assessed DAF-19 regulation …

Potential Role Of Pctaire-2, Pctaire-3 And P-Histone H4 In Amyloid Precursor Protein-Dependent Alzheimer Pathology, Dale Chaput, Lisa Kirouac, Stanley M. Stevens Jr., Jaya Padmanabhan

Molecular Biosciences Faculty Publications

Amyloid Precursor Protein (APP) is regulated in a mitosis-specific manner and plays a role in proliferative signaling in cells. Though APP-derived Aβ generation has a well-established role in neurodegeneration, the mechanistic role of APP in this process is not fully understood. Here, we performed an unbiased, comprehensive analysis of the phosphoproteome signature in APP-null neuroblastoma cells (B103) compared to those expressing APP-695 isoform (B103-695) to determine if APP expression affects protein phosphorylation. Stable isotope labeling by amino acids in cell culture (SILAC) followed by mass spectrometry-based phosphoproteomic analysis with PolyMAC identified a total of 2,478 phosphopeptides in the B103 and …

Dna Repair Deficiency In Huntington's Disease Fibroblasts And Induced Pluripotent Stem Cells, Peter Anthony Mollica

Biological Sciences Theses & Dissertations

Mutant huntingtin protein (mhtt)– the protein responsible for cellular dysfunction in Huntington’s disease (HD) –is a product of an expanded trinucleotide repeat (TNR) cytosine-adenine-guanine (CAG) sequence in exon 1 of the huntingtin (HTT) gene. The pathology of HD has been extensively researched; however, the mechanism by which the disease-causing TNR expansions occur in somatic cells remains elusive. Interestingly, HD has often been referred to a ‘DNA repair disease’, even though DNA repair dysfunction in situ has not been identified. We hypothesized that presence of the mhtt protein affects the expression of DNA repair genes used to address DNA repair, ultimately …

Evaluation Of Inhibitors Of Histone Deacetylases As Potential Neurotrophic Agents, Surabhi Shukla

Electronic Theses and Dissertations

The inhibitors of histone deacetylases (HDACs) have shown promising neuroprotective and neuroactive properties. A set of pan- and isoform-specific HDAC inhibitors were evaluated for neurotrophic activity on Neuroscreen-1 (NS-1) cells, a subclone of PC-12 (rat pheochromocytoma) cells.

The HDAC inhibitors were tested alone and in combination with nerve growth factor (NGF). An in vitro method has been standardized that measures neurite outgrowth along with cytotoxicity of test compounds in a single assay. The neurotrophin signaling pathways were interrogated with selective inhibitors of MEK1/2 (PD98059/U0126) PI3K (LY294002) and TrkA (GW441756) and phosphorylation of target kinases. Associated factors namely, acetylation of histones …

A Comprehensive Study Of The Effects Of Neurotoxins On Noradrenergic Phenotypes, Neuronal Responses And Potential Intervention By Antidepressants In Noradrenergic Cells, Yan Wang

Electronic Theses and Dissertations

It has been reported that locus coeruleus (LC) degeneration precedes the degeneration of other neurons in the brain in some neurodegenerative diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the precise mechanisms of neurodegeneration remain to be elucidated. N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) has been widely used as a noradrenergic neurotoxin in the development of AD and PD animal models for specific LC degeneration. However, the precise mechanism of action of DSP4 remains unclear. An increased systemic DNA damage caused by neurotoxin or oxidative stress has been found to be related to the pathogenic development of neurodegeneration. The process of neurodegeneration …