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Mind the Gap: Modeling Synaptic Development and Degeneration in Caenorhabditis elegans
Massengale, Molly Birrer
Massengale, Molly Birrer
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Abstract
The nervous system is composed of a complex network of neural circuits, relying on synaptic connections throughout to ensure proper signal transmission. Disorders of the nervous system typically fall into two categories, developmental disorders, failure of the system to properly form circuits, or senile disorders, failure of the system to properly maintain their circuits. As such, the formation, modification, and maintenance of synaptic connections is crucial to nervous system function, and a failure in any stage may lead to disease. Here we will use C. elegans to look at both sides of the process, examining the molecules important in the development of synapses, as well as examining the consequences on synaptic maintenance found in tauopathies, a class of neurodegenerative disorders. Synaptic development is a multi-step dynamic process, relying on a precise balance between adhesion-mediated stability and calcium-driven expansion. In chapter III, we show that synaptic expansion relies on the presence of the C. elegans ortholog of the calcium and integrin binding protein, CALM-1. We show that mutations in a predictive phosphorylation site of CALM-1 result in over-elongated synapses, suggesting that phosphorylation of CALM-1 might be necessary for proper synaptic growth and maintenance. In chapter IV, we show that the C. elegans neuromuscular junction can be used to model tauopathies, a subset of neurodegenerative disorders defined by the presence of abnormally aggregated clusters of tau. We show that expression of wildtype human 2N4R tau protein in the GABAergic motor neurons is well-tolerated, with no effects on synapse size, shape, or number. In contrast, expression of two mutated variants of human tau, a known disease-causing variant, P301, and an aggressively assembling variant, 3PO, induced progressive synaptic loss associated with the animal aging, notably without causing other forms of neurodegeneration, such as cell death or axon degradation. We show that synaptic loss is not merely a loss of vesicle trafficking, as use of another marker for synaptic active zones also demonstrated progressive synaptic loss in tau variant animals. Finally, we show that synaptic loss is not limited to the GABAergic motor neurons, as expression of mutant tau in another subset of neurons, the cholinergic neurons, also induced progressive synaptic loss. In Chapter V we look to further expand our model, by examining the consequences of genetic and chemical modifiers on the synaptic loss phenotype shown in mutant tau variants. We show that our model of synaptic degeneration can be used to screen genetic risk factors for tauopathies, as loss of function of a proposed Alzheimer’s disease risk factor, ptp-3, strongly enhanced the synaptic loss seen in tau mutant animals. We also show that expression of a risk factor for a primary tauopathy, Progressive Supranuclear Palsy, induced axon defects that were significantly enhanced by the presence of P301 tau, indicating the utility of our model to look beyond just synaptic consequences of tauopathy risk factors. Additionally, we show that our model can be used to screen for chemical modifiers of tauopathies, as we show that treatment of animals with a proposed tau aggregation inhibitor, ANTC15, partially rescues the synaptic loss in 3PO and P301 animals. Finally, in Chapter VI we begin to examine potential mechanisms of tau-mediated synaptic degeneration. We show that synaptic loss is not due to interference with the endogenous C. elegans tau-like protein, ptl-1, and that disruption of the normal method of calcium driven synaptic expansion does not significantly alter the synaptic loss phenotype, suggesting that the loss of synapses is a result of a toxic gain of function consequence of the addition of the mutated tau variants. Finally, we show that any interference with microtubule stability, through the over stabilization or destabilization of tubulin, is sufficient to induce a progressive decrease in synapses, suggesting that the synaptic loss seen in tau mutant animals may be a result of the mutation interfering with tau’s ability to bind and stabilize microtubules. Overall, this report strengthens our understanding of synaptic development, homeostasis, and age-related declines. More importantly, it establishes the first C. elegans model where we can examine synapse degeneration as a function of aging as it relates to human disease.
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Date
2022-12-31
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University of Kansas
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Keywords
Neurosciences, Molecular biology, Biology, aging, neural degeneration, synapse, tau