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Thesis (Ph. D.)--University of Wisconsin--Madison, 1968. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliography.

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Cheng, Tat Cheung. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 181-188). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease characterizeby devastating symptoms, such as muscle weakness, paralysis, and death within 5 years of disease onset. Mutations in human (VAMP)-associated protein B (hVAPB) gene cause ALS8. Interestingly, the Drosophila VAPB (DVAP) is required at the Drosophila larval neuromuscular junction (NMJ), to control bouton morphology. In Pennetta’s lab Drosophila Sac1, a phosphoinositide-4- phosphate (PI4P) phosphatase, was identified during a genome-wide yeast twohybrid screen, as a DVAP binding partner. VAP plays a role in regulating PI4P turnover in yeast and phosphoinositides are implicated in some neurodegenerative processes. In this PhD thesis, Sac1-DVAP interaction is used as the starting point to identify the mechanism that is altered when DVAP function is impaired. Thus, the possibility that the cellular pathways regulated by PI4P are affected in VAPB-mediated neurodegeneration was explored. First, the Sac1-DVAP association was confirmed in vitro by coimmunoprecipitation. Subsequently, we found that these two proteins colocalize in vivo at the ER membranes. Then, immunohistochemical analysis of Drosophila larval NMJ revealed that Sac1 and DVAP are involved in similar pathways. They both have a function in microtubule stabilization in the presynaptic boutons and axonal vesicle transport at the presynaptic compartment. They also seem to contribute to the spectrin-actin cytoskeleton stabilization at the postsynaptic compartment of the NMJ. Lastly, we reported that reduced levels of Sac1 phosphatase cause progressive neurodegeneration. Moreover, Sac1 is trapped into cytosolic aggregates induced by the expression of the ALS8-mutant allele of DVAP, and it does not localize to its original place in the cell. All together these results suggest that in ALS8 hVAPB seems to have a dominant negative effect on Sac1. Sac1 mislocalization could inhibit the dephosphorylation of PI4P. This PhD work further confirms Sac1-DVAP interaction and it suggests a mechanism underlying ALS8 pathogenesis, supporting the idea that altered metabolism of phosphoinositides can cause neurodegeneration.

"August 2002." Bibliography: p. 157-169. Analysis of the expression of Drosophilia cyclin EII through development show that it was present during larval development and oogenesis, implying a role for DmcycEII outside of early embyogenesis. Ectopic expression analyses using full-length DmcycE proteins as well as N- and C-terminal deletions of DmcycEI, revealed that DmcycEII and N-terminal deletions were able to drive all G1 cells within the morphogenetic furrow of the eye imaginal disc into S phase, while a C-terminal deletion of DmcycEI could not. These results show the DmcycEII is more potent than DmcycEI in driving cells into S phase and that the N-terminal region of DmcycEI contains a negative regulatory domean., suggesting that an inhibitor is present in the posterior morphogenetic furrow that binds to DmcycEI N-terminus and inhibits DmcycEI function. To identify the DmcycEI specific inhibitor, genetic interaction and yeast-2 hybrid screens were undertaken, and an enhancer CG7394, encoding a MAGUK homologue was identified for further study.

Errata pasted onto back page. Bibliography: p. 133-149. The RhoGEF activity of PBL is shown to be acting predominantly by the activation of Rho1 and downstream signaling pathways required for contractile ring function during cytokinesis. Genetic evidence suggests this could be through the activation of Diaphanous (an FH protein) to reorganize the actin cytoskeleton, as well as through the activation of Rho-kinase which results in the phosphorylation, and activation of myosin. Highlights a possible role for PBL during contractile ring function at a later stage that previously thought. Genetic interaction screens were employed to identify regulators of PBL activity during cytokinesis. CDK1 was identified genetically as a candidate for regulating PFB activity, but functional studies in vivo showed that this regulation was not by direct phophorylation of the PBK consensus CDK1 suites tested. Further screening has identified other possible components pf PBL signaling pathways, but a role during cytokinesis for these interactors remains to be confirmed. The eye phenotypes described provide ideal systems for the identification of components of PBL signaling pathways in Drosophila. The high level of conservation in the mechanism of cytokinesis from yeast to mammals would also suggest that the identified interactors would most likely represent components of cytokinesis pathways in all eukaryotes.

Errata pasted onto back page. / Bibliography: p. 133-149. / 149 p., [29] leaves of plates : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The RhoGEF activity of PBL is shown to be acting predominantly by the activation of Rho1 and downstream signaling pathways required for contractile ring function during cytokinesis. Genetic evidence suggests this could be through the activation of Diaphanous (an FH protein) to reorganize the actin cytoskeleton, as well as through the activation of Rho-kinase which results in the phosphorylation, and activation of myosin. Highlights a possible role for PBL during contractile ring function at a later stage that previously thought. Genetic interaction screens were employed to identify regulators of PBL activity during cytokinesis. CDK1 was identified genetically as a candidate for regulating PFB activity, but functional studies in vivo showed that this regulation was not by direct phophorylation of the PBK consensus CDK1 suites tested. Further screening has identified other possible components pf PBL signaling pathways, but a role during cytokinesis for these interactors remains to be confirmed. The eye phenotypes described provide ideal systems for the identification of components of PBL signaling pathways in Drosophila. The high level of conservation in the mechanism of cytokinesis from yeast to mammals would also suggest that the identified interactors would most likely represent components of cytokinesis pathways in all eukaryotes. / Thesis (Ph.D.)--University of Adelaide, Dept. of Molecular Biosciences, 2002?

"August 2002." / Bibliography: p. 157-169. / xi, 169 p. : ill. (some col.), plates (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Analysis of the expression of Drosophilia cyclin EII through development show that it was present during larval development and oogenesis, implying a role for DmcycEII outside of early embyogenesis. Ectopic expression analyses using full-length DmcycE proteins as well as N- and C-terminal deletions of DmcycEI, revealed that DmcycEII and N-terminal deletions were able to drive all G1 cells within the morphogenetic furrow of the eye imaginal disc into S phase, while a C-terminal deletion of DmcycEI could not. These results show the DmcycEII is more potent than DmcycEI in driving cells into S phase and that the N-terminal region of DmcycEI contains a negative regulatory domean., suggesting that an inhibitor is present in the posterior morphogenetic furrow that binds to DmcycEI N-terminus and inhibits DmcycEI function. To identify the DmcycEI specific inhibitor, genetic interaction and yeast-2 hybrid screens were undertaken, and an enhancer CG7394, encoding a MAGUK homologue was identified for further study. / Thesis (Ph.D.)--University of Adelaide, Dept. of Molecular Biosciences, 2002

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