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The role of SNX18 in modulating endocytic trafficking and deleterious effect of Aβ oligomers in synaptic vesicle trafficking : 세포내 수송과정에서 SNX18의 역할과 시냅스낭 순환과정에서의 Aβ oligomers의 유해한 효과에 관한 연구
DC Field | Value | Language |
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dc.contributor.advisor | 장성호 | - |
dc.contributor.author | 박주현 | - |
dc.date.accessioned | 2017-07-14T01:41:09Z | - |
dc.date.available | 2017-07-14T01:41:09Z | - |
dc.date.issued | 2013-02 | - |
dc.identifier.other | 000000008525 | - |
dc.identifier.uri | https://hdl.handle.net/10371/122240 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 : 의과학과 의과학 전공, 2013. 2. 장성호. | - |
dc.description.abstract | SNX18 and SNX9 are members of a subfamily of sorting nexin (SNX) proteins with the same domain structure. Although a recent report showed that SNX18 and SNX9 localize differently in cells and appear to function in different trafficking pathways, concrete evidence regarding whether they act together or separately in intracellular trafficking is still lacking. Here, I found that SNX18 has a similar role to SNX9 in endocytic trafficking at the plasma membrane, rather than having a distinct role. SNX18 and SNX9 are expressed together in most cell lines, but to a different extent. Like SNX9, SNX18 interacts with dynamin and stimulates the basal GTPase activity of dynamin. It also interacts with neuronal Wiskott-Aldrich syndrome protein (N-WASP) and synaptojanin, as does SNX9. SNX18 and SNX9 can form a heterodimer and colocalize in tubular membrane structures. Depletion of SNX18 by small hairpin RNA inhibits transferrin uptake. SNX18 successfully compensates for SNX9 deficiency during clathrin-mediated endocytosis and vice versa. Total internal reflection fluorescence microscopy in living cells shows that a transient burst of SNX18 recruitment to clathrin-coated pits coincides spatiotemporally with a burst of dynamin and SNX9. Taken together, these results are suggested that SNX18 functions with SNX9 in multiple pathways of endocytosis at the plasma membrane and that they are functionally redundant.
The second part of my dissertation, I studied the effects of soluble Aβ oligomers in the synaptic vesicle (SV) trafficking. Aβ oligomers are known to be correlated well with many early aspects of Alzheimer's disease (AD) pathogenesis. Although considerable evidence supports the link between Aβ oligomers and postsynaptic dysfunction, the effects of Aβ oligomers in presynaptic function continue to be revealed. The current study demonstrated that acute treatment with nanomolar concentration of Aβ oligomers results in a decrease of the recycling pool while the resting vesicle pool increases concomitantly in cultured hippocampal neurons. SV endocytosis and the regeneration of fusion-competent vesicle are also severely impaired. Furthermore, the release probability of the readily-releasable pool (RRP) is increased and the recovery rate after depletion of RRP is significantly delayed. All deficits are prevented by the antibody against Aβ, 6E10. The synaptojanin expression level is increased by Aβ oligomers, but Ca2+ clearance rate is not affected. The endocytic deficits by Aβ oligomers are fully restored by phosphatidylinositol-4-phosphate-5-kinase type I-γ expression while pool size alteration is recovered by inhibition of calpain-CDK5-mediated pathway, suggesting that two distinct downstream pathways involves in Aβ oligomers-induced presynaptic dysfunction. Together, my results suggest that Aβ oligomers cause defects in multiple steps of SV trafficking via different downstream pathways, which may affect presynaptic efficacy leading to synaptic dysfunction associated with AD. | - |
dc.description.tableofcontents | Abstract i
Contents iv List of figures v List of abbreviations viii General Introduction 1 Chapter 1 SNX18 shares a redundant role with SNX9 and modulates endocytic trafficking at the plasma membrane 4 Introduction 5 Material and Methods 9 Results 18 Discussion 42 Chapter 2 Deleterious effects of soluble Aβ oligomers in the multiple steps of synaptic vesicle trafficking 46 Introduction 47 Material and Methods 50 Results 58 Discussion 82 General Discussion 85 References 88 Abstract in Korean 107 Acknowledgements 111 | - |
dc.format | application/pdf | - |
dc.format.extent | 5032497 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | SNX18 | - |
dc.subject | SNX9 | - |
dc.subject | CME | - |
dc.subject | dynamin | - |
dc.subject | membrane tubulation | - |
dc.subject | Alzheimer’s disease | - |
dc.subject | soluble Aβ oligomers | - |
dc.subject | synaptic dysfunction | - |
dc.subject | presynaptic function | - |
dc.subject | synaptic vesicle (SV) trafficking | - |
dc.subject | phosphatidylinositol-4 | - |
dc.subject | 5-bisphosphate (PIP2) | - |
dc.subject | cyclin-dependent kinase 5 (CDK5) | - |
dc.subject.ddc | 610 | - |
dc.title | The role of SNX18 in modulating endocytic trafficking and deleterious effect of Aβ oligomers in synaptic vesicle trafficking | - |
dc.title.alternative | 세포내 수송과정에서 SNX18의 역할과 시냅스낭 순환과정에서의 Aβ oligomers의 유해한 효과에 관한 연구 | - |
dc.type | Thesis | - |
dc.contributor.AlternativeAuthor | PARK Joohyun | - |
dc.description.degree | Doctor | - |
dc.citation.pages | viii, 110 | - |
dc.contributor.affiliation | 의과대학 의과학과 | - |
dc.date.awarded | 2013-02 | - |
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