Ganglioside expression and function in development and disease
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This thesis dissertation examines the role of gangliosides in neocortical development and in genetic brain disease. The morphological changes that ferret neocortical pyramidal neurons undergo during basilar dendritic growth in vivo and the concomitant temporal and spatial pattern of six closely related gangliosides, including GM2, is described in Chapter 2. Only GM2 ganglioside, which was localized to vesicles within the somatodendritic region of pyramidal neurons, showed expression coincident with dendrite initiation. In Chapter 3, the functional role of gangliosides in dendrite initiation is tested. Partial inhibition of ganglioside synthesis prior to the onset of conspicuous dendrite outgrowth with N-butyldeoxynojirimycin (NB-DNJ) prevented the majority of pyramidal neurons from initiating the formation of basilar dendrites and accordingly most of these neurons displayed an immature phenotype. The addition of exogenous GM2 ganglioside was sufficient to protect pyramidal neuron morphology from the effects of the inhibitor. When inhibition was started after basilar dendritogenesis began, morphology was unaffected suggesting a restricted period of ganglioside involvement in this process.;Mechanisms regulating ganglioside expression and trafficking remain poorly understood. One way to approach this issue is to overexpress or ectopically express gangliosides---events that occur spontaneously in NPC. As shown in Chapter 4, NPC is caused by mutations affecting the protein NPC1 resulting in intraneuronal accumulation of unesterified cholesterol, and GM3 and GM2 gangliosides. This storage material predominantly resides in late endosomes/lysosomes suggesting that NPC1 trafficks gangliosides and unesterified cholesterol from these organelles. The well-documented consequence of overexpressing GM2 ganglioside, namely the initiation of ectopic dendrite growth, was extended to include the mouse and demonstrated that this capacity for new primary dendrite initiation increases with phylogenetic complexity. Finally, Chapter 5 describes that the administration of NB-DNJ to mice and cats with NPC in an attempt to reduce ganglioside storage by substrate deprivation. This approach resulted in diminution of neuronal storage, amelioration of neurological disease, and prolongation of life span in NPC mice. In summary, my findings advance our understanding of ganglioside biology including both the function of GM2 in pyramidal neuron dendritogenesis and the intraneuronal trafficking of GM3 and GM2 gangliosides by NPC1.