Life Sciences 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. …

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 …

Elucidating The Consequence And Cause Of Microrna Dysregulation In Amyotrophic Lateral Sclerosis (Als), Zachary C. E. Hawley

Electronic Thesis and Dissertation Repository

Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neurodegenerative disorder with an average life expectancy of 2-5 years post-diagnosis. Common pathological features associated with ALS are the formation of cytoplasmic inclusions of intermediate filaments and RNA-binding proteins within motor neurons. The formation of intermediate filament cytoplasmic inclusions is believed to be driven by a loss of stochiometric expression between five neuronal intermediate filament proteins—NFL, NFM, NFH, INA and PRPH—where there is a selective suppression of the steady-state levels of NEFL, INA and PRPH mRNA. Further, three RNA-binding proteins—TDP-43, FUS and RGNEF—have been shown to co-aggregate with each other in …

Investigating Cognitive Impairment In Tdp-43 Mouse Models Of Ftd-Als Using Automated Touchscreens, Keon Coleman

Electronic Thesis and Dissertation Repository

TAR-DNA-binding protein 43 (TDP-43) misfolding and aggregation is a major pathological hallmark of frontotemporal dementia-amyotrophic lateral sclerosis (FTD/ALS). FTD/ALS is characterized by motor and cognitive impairment, with cognitive impairment frequently reported before the onset of classical motor symptoms. Yet, treatment for cognitive decline in FTD/ALS is lacking, and robust cognitive phenotypes related to TDP-43 proteinopathy have not been established for most mouse models of FTD/ALS. Herein, we used automated touchscreen technology to assess executive function (affected in FTD/ALS) in male TDP-43^Q331Klow and ^-G348C FTD/ALS transgenic mice. The touchscreen pairwise visual discrimination task revealed impairments in 4-5-month-old TDP-43^Q331Klow and …

Protocol Development And Optimization For Rnls Mouse Characteristic Assessment, Hasan Farid

Browse all Theses and Dissertations

Protocol development and optimization are vital in the scientific method process. By having accurate protocols, one can properly assess the characteristics of their animal model for any given experiment. One animal newly adopted in our lab was the novel regulatable nuclear localization sequence (rNLS) mouse model. This novel mouse model displays symptoms of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD), after the accumulation of the hTDP-43 (TAR DNA-binding protein 43) aggregate in the central nervous system. The expression of this protein occurs after the removal of deoxycycline from the mouse’s food source. Once the removal of the drug, this …

The Leucine-Rich Domain Of Rgnef: A Modifier Of Tdp-43 Toxicity In Drosophila Melanogaster., Benjamin Martin Withers

Electronic Thesis and Dissertation Repository

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive degeneration of motor neurons. Rho Guanine Nucleotide Exchange factor (RGNEF) like other RNA-binding proteins, has been observed to form inclusions in the spinal cord motor neurons of both sporadic and familial cases of ALS. RGNEF has been determined to be a pro-survival factor under stress conditions. When comparing expression of different constructs of RGNEF in HEK293T cells, a Leucine-rich domain containing fragment of RGNEF (L-Rich) was found to form aggregates under metabolic stress that co-aggregated with TDP-43, another ALS-linked RNA-binding protein.

In this thesis, I used both …

Investigating The Role Of An Sk Channel Activator On Survival And Motor Function In The Sod1-G93a, Als Mouse Model, Matthew Thomas Dancy

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Amyotrophic Lateral Sclerosis (ALS) is a fatal, adult-onset progressive degenerative motor neuron disease that is characterized by muscle atrophy and weakness due to the loss of upper and lower motor neurons. Average survival time for individuals diagnosed with the disease is three to five years; currently there is no cure and only one drug approved by the Food and Administration (FDA). Scientists have proposed various theories in order to solve the mystery which surrounds ALS. One of these theories hypothesizes how hyperexcitability and excitotoxicity leads to the death of motor neurons. In this study, we will address ways of combatting …

Regulation Of The Cystine/Glutamate Antiporter And Its Contribution To Neuronal Death, Rebecca Albano

Dissertations (1934 -)

The aim of this thesis is to better understand the regulation of the cystine/glutamate antiporter (system xc-) and its role in regulating neuronal survival and death. Expressed primarily on astrocytes, system xc- takes up cystine and releases glutamate in a 1:1 ratio. Cystine uptake is the rate-limiting step in glutathione synthesis, the brain’s main antioxidant. Glutamate released into the extrasynaptic space can regulate neuronal function; however excessive glutamate release can cause excitotoxicity. The dual actions of system xc- make it of interest in many neurodegenerative diseases where oxidative stress and excitotoxicity are involved. We investigated the regulation of system xc- …

Sk Channel Clustering In Sod1-G93a Motoneurons, Saihari Shekar Dukkipati

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Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease that currently has no cure and extremely limited treatment options. The specific mechanisms that underlie motoneuron degeneration and death, which are classical features of this disease, are mostly unknown. This thesis tests the hypothesis that small-conductance calcium-activated potassium channels (SK) may be downregulated in ALS motoneurons, as suggested by computational modelling. SK channel expression was measured in spinal alpha-motoneuron cell bodies or somata of wildtype (WT) and mutant (mt) SOD1-G93A mice, a transgenic animal model of ALS. Quantitative immunohistochemical analysis of the developmental expression of SK channel isoforms SK2 and SK3 …

Multichannel Characterization Of Brain Activity In Neurological Impairments, Yalda Shahriari

Biomedical Engineering Theses & Dissertations

Hundreds of millions of people worldwide suffer from various neurological and psychiatric disorders. A better understanding of the underlying neurophysiology and mechanisms for these disorders can lead to improved diagnostic techniques and treatments. The objective of this dissertation is to create a novel characterization of multichannel EEG activity for selected neurological and psychiatric disorders based on available datasets. Specifically, this work provides spatial, spectral, and temporal characterizations of brain activity differences between patients/animal models and healthy controls, with focus on modern techniques that quantify cortical connectivity, which is widely believed to be abnormal in such disorders. Exploring the functional brain …

Mechanism Of Inhibition Of The Glua2 Receptors By N-3 Derivatives Of 2,3-Benzodiazepines With C-4 Methyl Group, Congzhou Wang

Legacy Theses & Dissertations (2009 - 2024)

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are one of the three subtypes of ionotropic glutamate receptors. AMPA receptors mediate fast synaptic neurotransmission in the central nervous system (CNS). Over-activation of calcium permeable AMPA receptors causes intracellular calcium overload, which leads to neurodegeneration and cell death. As such, AMPA receptors have been implicated in a number of neurological disorders and diseases, such as epilepsy, amyotrophic lateral sclerosis (ALS), and Parkinson's disease. 2,3-Benzodiazepine derivatives (or GYKI compounds) are a group of structurally similar compounds synthesized as inhibitors of AMPA receptors, and they have been used as potential drug candidates for the treatment of various …

Molecular Expression Of Neuroprotective And Neurodestructive Signaling Systems Following Axotomy-Induced Target Disconnection: Relevance To Als, Melissa Marie Haulcomb

Dissertations

Amyotrophic Lateral Sclerosis (ALS) is the most common adult motoneuron (MN) degenerative disease. Discovery of a portion of familial cases with a mutation in the gene superoxide dismutase 1 (SOD1) gene led to the development of a transgenic mouse model. Pre-symptomatic SOD1 mice show no symptoms well into adulthood, however once symptom onset has occurred they display pathological hallmarks of ALS. The initial pathological event is loss of neuromuscular junctions in the lower limbs and therefore the die-back theory of ALS, suggests disconnection from the target musculature leads to MN degeneration. Our lab utilizes a peripheral nerve injury model to …