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Roles of FcγRIIb signaling pathways in the pathogenesis of Parkinson’s disease
| DC Field | Value | Language |
|---|---|---|
| dc.contributor.advisor | 박상면 | - |
| dc.contributor.author | 최유리 | - |
| dc.date.accessioned | 2019-04-01T16:42:19Z | - |
| dc.date.available | 2019-04-01T16:42:19Z | - |
| dc.date.issued | 2019--2 | - |
| dc.identifier.other | 28551 | - |
| dc.identifier.uri | https://dspace.ajou.ac.kr/handle/2018.oak/15208 | - |
| dc.description | 학위논문(박사)--아주대학교 일반대학원 :의생명과학과,2019. 2 | - |
| dc.description.tableofcontents | I. ITRODUCTION 1 THEME I. FCΓRIIB MEDIATES THE INHIBITORY EFFECT OF Α-SYN FIBRILS ON MICROGLIA PHAGOCYTOSIS 1 THEME II. PRION-LIKE PROPAGATION OF Α-SYN IS REGULATED BY THE FCΓRIIB/SHP-1/-2/C-SRC SIGNALING PATHWAY IN NEURON 3 II. METERIALS AND METHODS 6 1. Reagent and antibody 6 2. Constructs 6 3. Purification of recombinant α-syn and preparation of α-syn fibrils 7 4. Thioflavin T Assay and Tranmission Electoron Microscopy (TEM) 8 5. Generation of stable cell lines 8 6. Cell culture 9 7. In vitro phagocytosis assay 10 8. Preparation of ICs (immune complex) 10 9. Preparation of Brain lysate 11 10. Western blot 11 11. Coimmunoprecipitation 12 12. Quantitative Real-time RT-PCR 12 13. In vitro cell to cell transmission assay using dual chamber 13 14. Coculture assay 13 15. Confocal microscopy 13 16. Statistical analysis 14 III. RESULTS 15 THEME I. FCΓRIIB MEDIATES THE INHIBITORY EFFECT OF Α-SYN FIBRILS ON MICROGLIA PHAGOCYTOSIS 15 1. α-Syn fibrils inhibits microglial phagocytosis in a dose-dependent manner. 15 2. Immune Complexes (ICs)-induced phagocytosis is also inhibited by α-syn fibrils. 19 3. α-Syn fibrils inhibits ICs-induced signaling pathway by SHP-1 activation. 22 4. SHP-1 is essential for the inhibition of microglial phagocytosis by α-syn fibrils. 25 5. α-Syn fibrils activates SHP-1 by interacting with FcγRIIB. 28 THEME II. PRION-LIKE PROPAGATION OF Α-SYN IS REGULATED BY THE FCΓRIIB/SHP-1/-2/C-SRC SIGNALING PATHWAY IN NEURON 34 6. α-Syn fibrils bind to human FcγRIIB 34 7. FcγRIIB downstream signaling is involved in cell-to-cell transmission of α-syn 37 8. α-Syn fibrils induce the phosphorylation of SHP-1 and SHP-2 by interacting with FcγRIIB 42 9. SHP-1/-2 expressed in neurons mediate cell-to-cell transmission of α-syn 48 10. FcγRIIB-SHP-1/2 Downstream Signaling Is Involved in Lipid Raft-Dependent Endocytosis 53 11. Development of an in vitro model system to quantify the formation of Lewy body-like inclusions by cell-to-cell transmission of α-syn 56 12. FcγRIIB-SHP-1/-2 signaling pathway mediates the formation of Lewy body-like inclusion induced by cell-to-cell transmission of α-syn fibrils 61 13. α-Syn fibrils induced c-src activity through FcγRIIB-SHP-1/2 pathway. 65 14. c-Src mediate cell-to-cell transmission of α-Syn. 68 15. c-Src mediates the formation of Lewy body-like inclusion induced by cell-to-cell transmission of α-syn fibrils 70 16. c-Src is also involved in the release of α-syn and degradation of α-syn through the autophagy. 73 IV. DISCUSSION 76 THEME I. FCΓRIIB MEDIATES THE INHIBITORY EFFECT OF Α-SYN FIBRILS ON MICROGLIA PHAGOCYTOSIS 76 THEME II. PRION-LIKE PROPAGATION OF Α-SYN IS REGULATED BY THE FCΓRIIB/SHP-1/-2/C-SRC SIGNALING PATHWAY IN NEURON 77 V. CONCLUSION 83 REFERENCE 84 국문 요약 95 | - |
| dc.language.iso | eng | - |
| dc.publisher | The Graduate School, Ajou University | - |
| dc.rights | 아주대학교 논문은 저작권에 의해 보호받습니다. | - |
| dc.title | Roles of FcγRIIb signaling pathways in the pathogenesis of Parkinson’s disease | - |
| dc.type | Thesis | - |
| dc.contributor.affiliation | 아주대학교 일반대학원 | - |
| dc.contributor.department | 일반대학원 의생명과학과 | - |
| dc.date.awarded | 2019. 2 | - |
| dc.description.degree | Doctoral | - |
| dc.identifier.localId | 905166 | - |
| dc.identifier.uci | I804:41038-000000028551 | - |
| dc.identifier.url | http://dcoll.ajou.ac.kr:9080/dcollection/common/orgView/000000028551 | - |
| dc.description.alternativeAbstract | α-Synuclein (α-Syn) has been considered to be a key player of the pathogenesis of PD, and recent reports that prion-like propagation of misfolded α-syn released from neurons may play an important role in the progression of PD have led to increased attention to the studies elucidating the roles of extracellular α-syn in the CNS. Extracellular α-syn has also been reported to regulate microglial inflammatory response including phagocytosis. Here, I demonstrate that how α-syn fibrils inhibits microglial phagocytosis to take advantage of immune complexes-induced phagocytosis model. α-syn fibrils bound to FcγRIIB on microglia, inducing SHP-1 activation, further inhibiting microglial phagocytosis. Further, I show that FcγRIIB expressed in neurons functions as a receptor for α-syn fibrils and mediates cell-to-cell transmission of α-syn. SHP-1 /-2 and c-Src are activated downstream by α-syn fibrils through FcγRIIB and play an important role in cell-to-cell transmission of α-syn. Also, taking advantage of a newly developed co-culture system, I show that cell-to-cell transmission of α-syn induces intracellular Lewy body-like inclusion body formation and that the FcγRIIB/SHP-1/-2/c-src signaling pathway is involved in it. Therefore, the FcγRIIB-SHP-1/-2/c-src signaling pathway may be a novel therapeutic target for the progression of PD and an in vitro model system provides an efficient tool for further high throughput screening that can be used for developing a therapeutic intervention in PD. | - |
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