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研究生:王建翔
研究生(外文):Chien-Hsiang Wang
論文名稱:去泛素酶Leon/USP5控制泛素鍊動態平衡於果蠅神經肌肉交結後突觸分化
論文名稱(外文):The deubiquitinase Leon/USP5 controls polyubiquitin homeostasis in postsynaptic differentiation at Drosophila neuromuscular junction
指導教授:簡正鼎簡正鼎引用關係
指導教授(外文):Cheng-Ting Chien
學位類別:博士
校院名稱:國立陽明大學
系所名稱:神經科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2014
畢業學年度:103
語文別:英文
論文頁數:77
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具有神經傳導功能的突觸包含了前突觸的激活區(active zone)以及後突觸蛋白質聚集區(postsynaptic density),突觸的形成與分化需要許多不同的突觸蛋白質來構建前突觸及後突觸。不同神經迴路的突觸分化成熟時會有其固定大小,而調控突觸生長到適合大小的機制還不清楚。我們的研究發現果蠅的去泛素酶Leon整合性的控制果蠅神經肌肉交結後突觸的蛋白質來限制後突觸過度分化。在leon的突變體中,膜系豐富的後突觸質網(subsynaptic reticulum)異常的增厚以及更加緻密,接受神經傳導物質的穀氨酸受器(glutamate receptor)群落也異常的增大。這些現象說明leon突變神經肌肉交結的後突觸過度分化。此外未固定的泛素鍊及泛素鍊鍵結受質也大量累積在leon突變神經肌肉交結的後突觸說明了缺少leon使得泛素鍊的動態穩定受到影響。累積的未固定泛素鍊透過泛素受器Ubiquilin影響蛋白酶體降解蛋白質的能力,於是許多後突觸蛋白質累積在leon突變神經肌肉交結後突觸上造成更嚴重的過度分化。我們認為去泛素酶Leon透過調控未固定泛素鍊維持泛素鍊動態穩定來限制後突觸的分化使後突觸能分化到適當的大小。
Synapse is composed of presynaptic active zone and postsynaptic density (PSD), which align with each other to ensure neurotransmission. Synaptogenesis requires factors that function in multi-facets of synaptic differentiation. Well-differentiated synapse has its specific size. How synaptic differentiation is terminated to ensure proper synaptic size has not been clear. Here, we show that Leon, the Drosophila homolog of the deubiquitinase (DUB) USP5, constrains coordinately different processes of postsynaptic differentiation. At leon mutant neuromuscular junctions (NMJs), the subsynaptic reticulum (SSR) comprising extensively folded membranes, the PSD region, and the PSD-localized glutamate receptor (GluR) clusters dramatically over-differentiate. Ubiquitin chains of both free and substrate-conjugated forms accumulate at the postsynaptic site of leon mutants, indicating a defect in the ubiquitin homeostasis. Accumulated polyubiquitin chains in leon mutants induce over-differentiation of postsynapses through malfunction of the ubiquitin receptor Ubiquilin (Ubqn), leading to the inhibition of proteasomal degradation. Due to impairment of proteasomal degradation, accumulated postsynaptic proteins further enhance PSD and SSR over-differentiation in leon mutants. We propose that the deubiquitinase Leon maintains polyubiquitin homeostasis through gating the levels of polyubiquitin chains to coordinately restrain PSD and SSR differentiation in postsynapses.
Table of Contents
中文摘要…………………………………………………………………………iv
Abstract…………………………………………………………………………v
Introduction…………………………………………………………………1
Materials and Methods……………………………………………………7
Results…………………………………………………………………………12
Isolation of leon mutants……………………………………………12
Leon is ubiquitous expression and multiple tissues disorders show in leon mutants…………………………………………………………………………13
NMJs display morphological defect in loss of Leon…………14
Leon is a DUB…………………………………………………………………15
Expansion of SSR area, PSD regions and GluR clusters in leon mutants…………………………………………………………………16
Ultrastructural analysis of leon mutant boutons……………18
Postsynaptic requirement of leon in NMJ growth and postsynapse differentiation……………………………………………19
Impaired electrophysiological properties at leon mutant NMJs………………………………………………………………………………20
Free polyubiquitin chains promote postsynaptic differentiation………………………………………………………………21
Proteasomal degradation is blocked in leon mutants………23
Ubqn is required for SSR and PSD over-differentiation in leon mutants……………………………………………………………………24
Proteasomal subunits are increased in leon mutants by SILAC method for flies……………………………………………………25
Discussion………………………………………………………………………27
The deubiquitinase Leon is required for proper differentiation of postsynapses………………………………………27
Leon regulates the levels of free polyubiquitin chains at postsynaptic sites…………………………………………………………27
Proteasomal degradation of polyubiquitin conjugates is defective in leon mutants………………………………………………29
Mechanisms mediating Leon-controlled postsynaptic differentiation………………………………………………………………31
Ubiquitous Leon functions in brain and discs development……………………………………………………………………32
Speculation of Leon/and Ubqn/Ubiquilin 2 in human diseases…………………………………………………………………………33
Figures……………………………………………………………………………34
Figure 1. Characterization of leon mutants……………………34
Figure 2. Leon antibody and Leon expression pattern………35
Figure 3. Defects of brain lobes and wing discs in leon mutants……………………………………………………………………………36
Figure 4. Abnormal morphology of NMJ in leon mutants……37
Figure 5. Leon deubiquitinating activity………………………38
Figure 6. Polyubiquitin chains accumulated at postsynapse in leon mutants………………………………………………………………39
Figure 7. Expansion of SSR in leon mutant NMJs………………40
Figure 8. Expansion of PSD in leon mutant NMJs………………41
Figure 9. Expansion of SSR and synaptic sizes in leon mutants……………………………………………………………………………42
Figure 10. Requirement of Leon deubiquitinating activity in synapse growth……………………………………………………………44
Figure 11. Requirement of Leon deubiquitinating activity in postsynaptic differentiation………………………………………45
Figure 12. Postsynaptic leon in SSR and PSD differentiation………………………………………………………………46
Figure 13. Synaptic transmission properties in leon mutants…………………………………………………………………………48
Figure 14. Induction of free polyubiquitin chains by expression of UbAA…………………………………………………………49
Figure 15. Postsynaptic defects induced by K48-linked polyubiquitin chains………………………………………………………50
Figure 16. Compromised protein degradation in leon mutants…………………………………………………………………………51
Figure 17. Accumulation of postsynaptic proteins aggregated postsynaptic defects in leon mutants……………52
Figure 18. Proteasome activity assay and RNAi efficiency test………………………………………………………………………………53
Figure 19. Ubqn is required for SSR and PSD expansions in leon mutants…………………………………………………………………54
Figure 20. Ubqn mediates free polyubquitin chains accumulation in leon mutants…………………………………………55
Figure 21. Elevation of proteasome subunits in leon mutants…………………………………………………………………………57
Figure 22. Model of Leon function in postsynaptic differentiation in Drosophila NMJs…………………………………58
Tables……………………………………………………………………………59
Table 1. Chart shows elevation of proteasomal subunits in leon1/19-2 by SILAC method………………………………………………59
Table 2. Detail statistical data in all figures………………60
Reference…………………………………………………………………………69

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