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Endocytosis-Associated Guanine Nucleotide Exchange Factor Rabgef1 Facilitates the Biogenesis of Outer Segments in Mammalian PhotoreceptorsHargrove, Passley 23 February 2018 (has links)
<p> Rod and cone photoreceptors in the retina are polarized sensory neurons that possess uniquely modified primary cilium, called the outer segment, to capture photons. Circadian-mediated shedding and renewal of outer segment membrane discs requires extensive vesicular transport of protein cargo from the endoplasmic reticulum and Golgi to the base of the cilium. Endocytosis is vesicle transport process of capturing and/or recycling extrinsic components and is shown to occur in retina of early vertebrates, such as <i>Xenopus</i> laevis. In this thesis, I have explored the hypothesis that a critical endocytosis-associated protein Rabgef1 is critical for the genesis of photoreceptor outer segments in the mammalian retina. After demonstrating high expression of Rabgef1 concordant with photoreceptor maturation, I characterized morphology and function of retina from <i>Rabgef1</i>-loss of function (<i>Rabgef1</i><sup>–/–</sup>) mice. Though no gross defect was observed by histology and immunohistochemistry before eye opening (postnatal day 14), transmission electron microscopy demonstrated ultrastructural defects in photoreceptor outer segments by P8. Progressive, yet rapid, photoreceptor degeneration and near-complete ablation of the visual response were evident at and after P15. I show that the outer segment defect noted in <i>Rabgef1</i><sup>–/–</sup> mice was not due to defective ciliogenesis or trafficking of cargo proteins to the cilium. In concordance with other systems, Rabgef1 was enriched in purified endocytic vesicles from the retina and interacted with Rabaptin5, confirming its role in Rab5-mediated endocytosis. Curiously, <i>Rabgef1</i><sup>–/– </sup> photoreceptors accumulated enlarged vesicular/endosomal structures within the inner segment, similar to loss of function mutations in the yeast orthologue of Rabgef1, Vps9p. My studies provide the first evidence of an essential role of Rabgef1-mediated fusion and recycling of endocytic vesicles in the formation and/or renewal of outer segment membrane discs in the mammalian retina. Rabgef1 and other components of the endocytic pathway should therefore be considered as candidates for human retinopathies. </p><p>
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Aging, Stress, and Pathogenesis of Parkinson's Disease| Studies Using C. elegansCooper, Jason Fisk 14 April 2018 (has links)
<p> Parkinson’s disease (PD) is an adult onset neurodegenerative disease that is characterized by deficiencies in movement, cognition, and Lewy body neuropathology within the brain. Motor and cognitive deficiencies progressively worsen through the course of disease concurrent with increasing neuropathology and neurodegeneration. Approximately 10–15% of PD patients have a family history of PD with a confirmed genetic cause. Presently PD pathogenesis is incompletely understood and there are no treatments capable of halting or reversing this disease. The extended disease-course and age-dependent nature of PD, especially in genetic cases where a mutation is present from birth, affirm that aging itself is the most important risk factor for disease. We hypothesize that specific cellular changes that occur during the normal process of aging confer susceptibility to disease-causing mutations which, while tolerated at younger ages, contribute to disease with age. Accurate animal models of PD and aging provide the ability to elucidate disease mechanisms and explore novel strategies targeting the aging process. To test the role of aging in PD we utilize the nematode <i>Caenorhabditis elegans</i> because this animal has been used extensively to study animal aging at a cellular level. We confirm that disease phenotypes in genetic <i>C. elegans</i> models of PD such as neurodegeneration, protein aggregation, and mitochondrial deficits are proportional to this organism’s brief lifespan. This indicates that PD progresses according to biological age and not merely to chronological time. As a proof-of-principle we also show that delaying aging by mutation of the gene encoding the insulin-IGF receptor, <i>daf-2</i>, can rescue multiple deficits present in nematode models of PD. Overall we demonstrate that biological aging is a crucial for the development of various PD associated phenotypes and that delaying aging is sufficient to delay these phenotypes. Therefore targeting aging itself may be a sound strategy for the halting or the prevention of PD.</p><p>
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All for One But Not One for All| Excitatory Synaptic Scaling and Intrinsic Excitability are Coregulated by Camkiv, While Inhibitory Synaptic Scaling is Under Independent ControlJoseph, Annelise K. 29 November 2017 (has links)
<p> Despite being comprised of networks with extensive positive feedback, the brain is able to prevent runaway activity. Neural networks are remarkably good at maintaining an activity setpoint while still permitting learning-related or developmental plasticity. To accomplish the delicate balance between change and stability, neural networks employ a group of homeostatic negative feedback mechanisms. This suite of homeostatic mechanisms sense and adjust neuronal excitability to keep firing rates within some target range. To date, the most well described manner in which neurons homeostatically regulate their excitability is through adjustment of excitatory or inhibitory synaptic weights, or by modulating their intrinsic excitability. It is perplexing why the neuron should have several means to accomplish the same outcome. Experiments demonstrating the collaborative or solo induction of homeostatic mechanisms have provided only limited insight into how homeostatic signaling pathways are organized to generate and maintain firing rate set-points (FRSP).</p><p> In order for neurons to maintain a FRSP, deviations from this value must modulate an internal signal that subsequently triggers homeostatic mechanisms to restore excitability to its set-point. The CaMKIV pathway is a calcium-dependent signaling element that plays a crucial role in regulating excitatory synaptic strength. The CaMKIV cascade is highly sensitive to activity and can modulate transcription, making it an ideal candidate to integrate incoming activity and modulate the excitability of neurons. Therefore, the major aim of this thesis was to characterize the role of CaMKIV in inducing multiple forms of homeostatic plasticity in tandem. Here we leverage our expertise in measuring homeostasis in neocortical neurons <i>in vitro</i> to determine how manipulating the activation state of nuclear CaMKIV affects neuronal excitability. </p><p> We found that excitatory synaptic scaling and intrinsic plasticity were bidirectionally induced by manipulating CaMKIV activity even without any perturbations to network activity. In contrast, CaMKIV had no impact on inhibitory synaptic weights. Additionally, we found that CaMKIV activity bidirectionally regulated spontaneous firing rates. Taken together, our data suggests that CaMKIV activity is used by the neuron to monitor the firing set point and gate homeostatic mechanisms to correct for drift from this target. The data presented in this thesis contribute that excitatory synaptic scaling and intrinsic excitability are tightly coordinated through bidirectional changes in the same signaling pathway, while inhibitory synaptic scaling is sensed and regulated through an independent signaling mechanism. This body of work contributes to a better understanding of neuronal homeostasis and will hopefully help us determine how malfunctions in homeostatic plasticity contributes to neurological and neurodevelopmental disorders.</p><p>
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