Nervous System Diseases Commons^™

Can Mirna Be The Missing Link Between Parkinson’S Disease And Pesticides?, Fatma Gobba

Theses and Dissertations

Parkinson’s disease (PD) is a common neurodegenerative condition that leads to significant morbidity and a decline in the quality of life. It develops as a consequence of the loss of dopaminergic neurons in the substantia nigra pars compacta. Nevertheless, the development of PD is influenced by environmental factors, and the intricate nature of these relationships is further complicated by a multitude of factors, including the genetic backgrounds that are specific to populations and variations in environmental exposures, such as pesticides. Pesticides, consisting of a diverse family of chemicals commonly used in both agricultural and household settings to protect crops against …

Impairment Of The Glial Phagolysosomal System Drives Prion-Like Propagation Of Huntington’S Disease, Graham Davis

Theses and Dissertations

The ability of glia to tightly regulate neuronal health and homeostasis in the CNS is conserved across species. Yet, despite the ability to degrade protein aggregates, glia are vulnerable to the accumulation of neurotoxic amyloid aggregates during neurodegenerative disease progress, and even exacerbate their spread. A developing narrative highlights glia as a double-edged sword in neurodegenerative diseases: initially capable of dynamically responding to amyloid aggregate-ladened dying neurons but also capable of inducing chronic inflammation and creating seeding-competent amyloid oligomers. Thus, uncovering the mechanisms that allow glia to control aggregate deposition while preventing the neurotoxic effects and seed generation is vital …

A Preliminary Investigation Of Neuroantibody Levels, Prevalence, And Environmental Factors In Patients With Neurological Dysfunction, Jihan Azar

Theses and Dissertations

Nervous system damage comprises a large proportion of diseases worldwide. It is also the most difficult to diagnose. Biomarkers for nervous system damage are needed in order to diagnose these diseases early enough to allow for intervention. In this study, we recruited patients from two Egyptian hospitals with MCI, ET and NMS and health references. Serum autoantibody levels against neural proteins and heavy metals were analyzed and compared. Immunoglobulin G (IgG) antibodies against neurofilament H (NFH), Glial Fibrillary Acidic Protein (GFAP), Myelin Basic Protein (MBP) and alpha synuclein (a-SYN) and Immunoglobulin M (IgM) antibody against neurofilament light (NFL) were among …

Selective Gsk3Β Inhibition Mediates An Nrf2-Independent Anti-Inflammatory Microglial Response, Mohamed H. Yousef

Theses and Dissertations

Glycogen Synthase Kinase 3 (GSK3) is associated with the proinflammatory phenotype of microglia and has been shown to act in concert with Nuclear factor kappa B (NF-κB). . GSK3 is also a suppressor of Nuclear factor erythroid 2-related factor 2 (Nrf2), the principal regulator of redox homeostasis. Agreeing with the oxidative paradigm of aging, Nrf2 is often deregulated in parainflammatory and neurodegenerative diseases. In this study, we aimed to explore a multimodal disease-modifying utility of GSK3 inhibition, beyond neuronal proteopathologies, Furthermore, we aimed to underscore the difference in therapeutic value between the two GSK3 paralogs by isoform-selective chemical inhibition.

The …

Investigating Cannabinoid Type-1 Receptor (Cb1r) Positive Allosteric Modulators (Pams) In Mouse Models Of Overt Cannabimimetic Activity, Subjective Drug Effects, And Neuropathic Pain, Jayden Elmer

Theses and Dissertations

Chronic pain affects between 20 and 30 percent of the adult population in western countries and represents a wide array of specific etiologies (Berge, 2011). Neuropathic pain secondary to traumatic nerve injury, chemotherapeutic toxicity, or diseases (e.g., diabetes mellitus) is often refractory to conventional analgesics, with patients receiving less than 50% pain relief compared to placebo (Finnerup et al. 2010). The endocannabinoid system has shown potential as a therapeutic target for neuropathic pain wherein CB1 agonism via administration of exogenous agonists or pharmacological blockade of endocannabinoid catabolic enzymes exhibits efficacy in reversing allodynia in the chronic constriction injury (CCI) model …

Ndrg1 And Myelin-Related Disease: Alcoholism And Chemotherapy-Induced Neuropathy, Guy Harris

Theses and Dissertations

Alcohol use disorder (AUD) is a prevalent neuropsychiatric disease with profound health, social, and economic consequences. With an estimated 50% heritability, identifying genes that engender risk and contribute to the underlying neurobiological mechanisms represents an important first step in developing effective treatments. Gene expression studies are an important source of candidate genes for studying AUD, providing windows into the molecular machinery engaged by the brain in response to ethanol. Our laboratory has implicated N-myc down-regulated gene 1 (Ndrg1) as a potential candidate gene that modulates ethanol-induced changes in myelin-related gene expression and acute sensitivity to ethanol. Analysis of …

Exploring The Heteromeric Interface Of The 5-Ht2a-Mglu2 Receptor Complex, Mohamed Aarif Abdul Kareem

Theses and Dissertations

Schizophrenia is a serious mental disorder characteristic of several neurotransmitters including dopamine, serotonin, and glutamate being in imbalance. Early therapies focused solely on dopamine antagonism and second-generation antipsychotics focused on the dopamine and serotonin systems and their respective G protein coupled receptor (GPCR) proteins. Although debate for dimerization of certain classes of GPCR exist, the establishment of an mGlu2-5-HT_2A heterocomplex, which is implicated in schizophrenia is of interest. Previous studies have used a mutation-based approach to identify transmembrane domain 4 (TM4) as the domain responsible in mGlu2 for mediating heteromerization before narrowing down the individual amino acids responsible for …

Recovery From Visual Dysfunction Following Mild Traumatic Brain Injury Is Associated With Adaptive Reorganization Of Retinal Inputs To Lateral Geniculate Nucleus In The Mouse Model Utilizing Central Fluid Percussion Injury., Vishal C. Patel

Theses and Dissertations

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality nationwide. Prevalence of mild TBI (mTBI) vastly outnumbers more severe forms however the associated morbidity has only recently gained public attention. Visual dysfunction is a significant component of mTBI associated morbidity with recovery of function linked with improvement in global outcomes. Examination of sensory and motor pathways in other brain injury paradigms support that recovery is largely dependent on adaptive plasticity of remaining connections. Current examinations of visual function recovery following mTBI is limited to identifying evidence for recovery and objective evidence for adaptive plasticity is limited. Therefore, …

Role Of Sarm1 In Chronic Immune-Mediated Central Nervous System Inflammation, Kenneth E. Viar Ii

Theses and Dissertations

SARM1 is an injury-induced nicotinamide adenine dinucleotide nucleosidase (NADase) that was previously shown to promote axonal degeneration in response to traumatic, toxic, and excitotoxic stressors. This raises the question of whether a SARM1-dependent program of axonal degeneration is central to a common pathway contributing to disease burden in neurological disorders. The degree to and mechanism by which SARM1 inactivation decreases the pathophysiology of such disorders is of interest to establish the rationale to pursue SARM1 as a therapeutic target. In this study, we compare the course and pathology of experimental autoimmune encephalomyelitis (EAE) in Sarm1-knockout (KO) mice and wild-type …

Long-Term Effects Of Notch1 Signaling On Neural Stem Cells Following Traumatic Brain Injury, Cruz Sevilla Jr

Theses and Dissertations

Traumatic brain injury (TBI) is a devastating problem which stands as a leading cause of death and disability. The elderly is significantly affected by TBI, typically as the result of falls, and recovery is especially limited. This, in part, is associated with decreased tissue-specific stem cell regeneration and replacement of damaged cells in the aged brain. The diminished ability of the aged brain to recover is especially devastating after TBI, likely leading to permanent loss of sensory, motor, and cognitive functions. Studies have shown that the mature mammalian brain contains Neural Stem Cells (NSCs), found in specific regions of the …

Altered Axon Initial Segment Structure And Function In Inflammatory Disease, Kareem C. Clark

Theses and Dissertations

Axonal pathology is a key contributor to long-term disability in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), but the mechanisms that underlie axonal insults remain unclear. While most axonal pathologies characterized in MS are a direct consequence of myelin loss, we propose that axonal pathologies also occur independent of demyelination. In support of this idea, we recently reported that mice that develop experimental autoimmune encephalomyelitis (EAE), a model commonly used to mimic the pathogenesis of MS, exhibit a structural and functional disruption of the axon initial segment (AIS), a subdomain of the axon that …

Design, Synthesis, And Biological Screening Of Selective Mu Opioid Receptor Ligands As Potential Treatments For Opioid Addiction, Samuel Obeng

Theses and Dissertations

Today, more Americans die each year because of drug overdoses than are killed in motor vehicle accidents. In fact, in 2015, more than 33,000 individuals died due to an overdose of heroin or prescription opioids. Sadly, 40-60 % of patients on current opioid addiction treatment medications relapse. Studies have shown that the addiction/abuse liability of opioids are abolished in mu opioid receptor (MOR) knock-out mice; this indicates that the addiction and abuse liability of opioids are mainly mediated through MOR. Utilizing the “message-address concept”, the our laboratory reported a novel non-peptide, reversible MOR selective ligand 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α (isoquinoline-3-carboxamido)morphinan (NAQ). Molecular modeling …

A Mechanistic Study Of An Ipsc Model For Leigh’S Disease Caused By Mtdna Mutataion (8993 T>G), John P. Galdun

Theses and Dissertations

Mitochondrial diseases encompass a broad range of devastating disorders that typically affect tissues with high-energy requirements. These disorders have been difficult to diagnose and research because of the complexity of mitochondrial genetics, and the large variability seen among patient populations. We have devised and carried out a mechanistic study to generate a cell based model for Leigh’s disease caused by mitochondrial DNA mutation 8993 T>G. Leigh’s disease is a multi-organ system disorder that depends heavily on the mutation burden seen within various tissues. Using new reprogramming and sequencing technologies, we were able to show that Leigh’s disease patient fibroblasts …

Post-Tbi Hippocampal Neurogenesis In Different Tbi Models, Kaushal S. Patel

Theses and Dissertations

Traumatic brain injury (TBI) leads to short-term and long-term consequences that can cause many different life-long disorders. Studies of TBI have generally focused on the acute stage; however, it is now becoming important to investigate chronic responses following TBI as clinical reports of dementia and cognitive impairments have been linked to a history of TBI. Recent data have established that cognitive function is associated with hippocampal neurogenesis. Chronic injury induced changes in the brain may affect this endogenous process. Chronic responses following TBI include cell death pathways and inflammatory responses that are persistent in the brain for months to years …

The Effect Of Optogenetic Manipulation Of Ss Interneurons Within Malformed, Epileptogenic Cortex, Nicole Ekanem

Theses and Dissertations

A large percentage of individuals with intractable epilepsies have an accompanying cortical malformation, the underlying cellular mechanisms of which are poorly understood. It is known however that in an animal model for one such malformation, polymicrogyria, epileptogenesis occurs most easily from an adjacent area termed the paramicrogyral region (PMR). Previous studies implicate SS interneurons as a potential contributor to this pathology, which lead to our hypothesis: in PMR, SS interneurons exert a higher modulatory influence on excitatory pyramidal cells, as compared to the same by SS interneurons within homologous control cortex.

Using a freeze-lesion model for polymicrogyria in transgenic mice …

Axon Initial Segment Stability In Multiple Sclerosis, Suneel K. Thummala

Theses and Dissertations

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by inflammation and demyelination. In addition to these hallmark features, MS also presents with axonal pathology, which is likely responsible for the signs and symptoms of the disease. Although prominent in MS, axonal pathology is frequently considered a consequence of demyelination and not a primary event. This conclusion is consistent with demyelination inducing the loss of specific axonal domains, known as the nodes of Ranvier that are responsible for the propagation of action potentials along the axon. In contrast, we propose that axonal pathology associated with MS …