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Full-Text Articles in Medicine and Health Sciences
Transcriptional Regulation Of Metabolism And Synaptic Function In Neurons, Stephanie N. Fox
Transcriptional Regulation Of Metabolism And Synaptic Function In Neurons, Stephanie N. Fox
All ETDs from UAB
Mitochondrial dysfunction, transcriptional dysregulation, and protein aggregation are all unifying features of neurodegenerative disorders, including Parkinson’s Disease. Parkinson’s Disease is a debilitating movement disorder with no known cure, leading sci-entists to explore the underlying etiological contributors to neuronal dysfunction and loss to devise strategies for neuroprotection. Estrogen-related receptor gamma (ERRγ) is a member of a family of transcription factors which regulate the expression of mitochondrial genes. To determine whether ERRγ modulation can provide insight into transcriptional and mitochondrial dysfunction with neurodegeneration, the experiments in this thesis project determined 1) the importance of transcription of mitochondrial genes in disease as regu-lated …
Elucidating Pgc-1Α And Errγ Gene Regulation In Neurons, Kathlene Lanphear Joyce
Elucidating Pgc-1Α And Errγ Gene Regulation In Neurons, Kathlene Lanphear Joyce
All ETDs from UAB
Neuronal energy production is critical to the function of the entire central nervous system. Without enough ATP, neurons are not able to maintain their synaptic structure or activity, leading to a circuit-wide dysregulation, affecting movement and memory. The main process for ATP production in neurons is oxidative phosphorylation, which is supported by several proteins encoded by nuclear DNA. Transcription of nuclear DNA is regulated by DNA-binding transcription factors and co-activators which recruit other members of the transcription initiation complex to induce gene expression. While important basally, during neurodegenerative diseases such as Parkinson’s Disease, the transcription of these genes is altered …
Cns Antigen Presentation And Immune Cell Infiltration In An Α-Syn Model Of Parkinson Disease, Aubrey Michelle Schonhoff
Cns Antigen Presentation And Immune Cell Infiltration In An Α-Syn Model Of Parkinson Disease, Aubrey Michelle Schonhoff
All ETDs from UAB
Parkinson disease (PD) is a neurodegenerative movement disorder that is characterized by aggregated alpha-synuclein (a-syn), loss of dopaminergic neurons, and neuroinflammation. This neuroinflammation includes the activation of immune cells that reside in the CNS, such as microglia and border associated macrophages (BAMs), in addition to the infiltration of peripheral leukocytes and increased cytokine and chemokine production. Because of the involvement of both the innate and adaptive immune systems, we sought to investigate their interaction through antigen presentation and determine what role this played in disease progression. Using an a-syn based mouse model of PD, our studies have provided evidence via …
Pharmacodynamic Responses And Efficacies Associated With Lrrk2 Inhibition, Kaela Kelly
Pharmacodynamic Responses And Efficacies Associated With Lrrk2 Inhibition, Kaela Kelly
All ETDs from UAB
Parkinson’s disease (PD) is an age-related, progressive, movement disorder pathologically characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of proteinaceous aggregates, termed Lewy bodies, that are largely comprised of αSynuclein (αSyn). Missense mutations in the leucine-rich repeat kinase (LRRK2) gene are the most common genetic cause of PD and lead to gain-of-function increases in kinase activity. The G2019S-LRRK2 mutation is the most frequent mutation and elevates kinase activity by ~2-3 fold. Genetic and biochemical evidence suggest elevated LRRK2 kinase activity plays a pathogenic role in the development of PD, implicating LRRK2 …
Role Of Endogenous Tau In Lewy-Like Pathology, Lindsay Stoyka
Role Of Endogenous Tau In Lewy-Like Pathology, Lindsay Stoyka
All ETDs from UAB
Lewy Body Diseases (LBDs) are a group of disorders characterized by intracellular inclusions of misfolded alpha-synuclein (α-synuclein). Of these, Parkinson’s Disease (PD) is the most common neurodegenerative movement disorder, and Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative dementia. PD is characterized clinically by bradykinesia, resting tremor, rigidity, and postural instability. In addition, up to 80% of patients eventually develop dementia, termed Parkinson’s Disease Dementia (PDD). DLB is characterized by onset of dementia before or concurrently with parkinsonism. Currently, no disease-modifying therapies exist for either of these diseases. Lewy pathology is found in regions important for cognition …
From Pathology To Circuits: Loss Of Pink1 Function In Parkinson’S Disease, Rose Berthe Creed
From Pathology To Circuits: Loss Of Pink1 Function In Parkinson’S Disease, Rose Berthe Creed
All ETDs from UAB
Parkinson’s disease (PD) is the most common neurogenerative motor disorder, affecting over 10 million people worldwide. Clinically, PD is diagnosed by presentation of hypokinetic movements such as bradykinesia, rigidity, and resting tremor. Additionally, PD patients have non-motor symptoms that include anosmia, constipation, and hypophonia. Current therapeutics have been successful in treating many of the locomotor symptoms, however no therapies stop or slow disease progression and the effectiveness of current medications diminishes as the symptoms invariably become more severe over the course of many years. Histopathologically, PD diagnosis is confirmed postmortem by two pathological hallmarks: 1. loss of dopaminergic neurons in …
14-3-3 Proteins Regulate Mutant Lrrk2 Kinase Activity And Neurite Shortening, Nicholas Lavalley
14-3-3 Proteins Regulate Mutant Lrrk2 Kinase Activity And Neurite Shortening, Nicholas Lavalley
All ETDs from UAB
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common known cause of inherited Parkinson’s disease (PD), and LRRK2 is a risk factor for idiopathic PD. How LRRK2 function is regulated is not well understood. Recently, the highly-conserved 14-3-3 proteins, which play a key role in many cellular functions including cell death, have been shown to interact with LRRK2. In this study, we investigated whether 14-3-3s can regulate mutant LRRK2-induced neurite shortening and kinase activity. In the presence of 14-3-3θ overexpression, neurite length of primary neurons from BAC transgenic G2019S-LRRK2 mice returned back to wildtype levels. Similarly, 14-3-3θ overexpression …
Metabolic And Oxidative Regulation Of Neuronal Autophagy And Survival, Matthew Dodson
Metabolic And Oxidative Regulation Of Neuronal Autophagy And Survival, Matthew Dodson
All ETDs from UAB
Neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease and Huntington's disease are all characterized by metabolic dysfunction, increased oxidative damage to proteins and organelles, formation of proteinaceous inclusions, decreased autophagic and proteasomal function, and eventual neuronal and glial cell death. While our understanding of the mechanisms that underlie many of these pathologies is constantly growing, their exact cause, onset, interplay and progression still remain unclear. The gap between the description of disease pathologies and understanding the fundamental mechanisms of disease pathogenesis, progression and potential therapeutics to mitigate disease progression is still large. Based on the observation that altered glucose utilization, …
Innate Immunity Mechanisms In Parkinson Disease, Mark Moehle
Innate Immunity Mechanisms In Parkinson Disease, Mark Moehle
All ETDs from UAB
Parkinson disease (PD) is a late onset, progressive neurodegenerative movement disorder with cardinal symptoms of tremor at rest, bradykinesia, postural instability, and rigidity. These motor symptoms of PD are caused by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). However, despite PDs first modern observation in 1817, little is understood about the causes and molecular mechanisms behind dopaminergic neuron loss. The relatively weak understanding of pathological mechanisms has hindered the development of treatments to slow or halt the progression of PD. However, recently, mounting evidence from post-mortem, imaging, and retrospective studies suggest an important role …
The Role Of The Autophagy-Lysosome Pathway In In Vitro Models Of Neurodegeneration, Burton Mader
The Role Of The Autophagy-Lysosome Pathway In In Vitro Models Of Neurodegeneration, Burton Mader
All ETDs from UAB
Recent studies have provided strong evidence that alterations in protein degradation pathways, such as the autophagy-lysosome pathway (ALP), may contribute to neuronal dysfunction and death which lead to clinical symptoms diagnosed with various neurodegenerative diseases. Parkinson's disease (PD) is characterized by neuromuscular abnormalities resulting from the pathological loss of substantia nigra dopaminergic neurons and widespread detection of Lewy bodies, intracellular protein inclusions composed primarily of α-synuclein. Additionally, altered gene function regulating the expression of α-synuclein has been directly linked to the PD pathogenesis. Autophagy is an intracellular degradation process that when altered can lead to the accumulation neurotoxic proteins such …
Development Of An Adenoviral Vector Platform For Selective Gene Delivery To Neurons, Travis Benjamin Lewis
Development Of An Adenoviral Vector Platform For Selective Gene Delivery To Neurons, Travis Benjamin Lewis
All ETDs from UAB
Parkinson disease (PD) is a devastating movement disorder affecting between 500,000 and 1,000,000 individuals in the United States alone, and for which there is currently no cure. Therapies such as dopamine replacement help initially, but with disease progression these lose efficacy and do not alter the underlying degenerative process. Gene therapy is the delivery of exogenous genetic material to correct an underlying disorder. A major advantage of this approach is the ability to distribute potent therapies to specific targets over an extended duration, properties necessary for the treatment of progressive degenerative diseases such as PD. A number of clinical trials …
Cytokine Signaling In A Mouse Model Of Parkinson's Disease, Shuwen Cao
Cytokine Signaling In A Mouse Model Of Parkinson's Disease, Shuwen Cao
All ETDs from UAB
The protein alpha-synuclein (α-SYN), which is found in the Lewy bodies of dopaminergic (DA) neurons in the substantia nigra (SN), has an important role in the pathogenesis of Parkinson's disease (PD). Fcγ receptors (FcγR) are proteins present on the surface of microglia, which bind immunoglobulin G (IgG) and other ligands. Our studies in an AAV-synuclein mouse model of PD showed that over-abundance of α-SYN triggered the expression of NF-κB p65, and led to microglial activation and DA neurodegeneration; however, in mice deficient of gamma chain subunit of the Fc receptors (FcγR-/- mice), α-SYN-induced NF-κB signaling was blocked, while microglial activation …