軸突運輸與神經學疾病的關聯已受到仔細地研究。UNC-104/KIF1A是神經中突觸囊泡的主要運輸者，此分子馬達的缺陷與夏柯-馬利-杜斯氏症與遺傳性痙攣性下身麻痺(HSP)有關。在本實驗室先前發表的碩士論文(Zaira Wang, 王孟婕)中，兩種突觸缺陷株unc-17(e245) (乙醯膽鹼運輸蛋白)與eat-4(ky5) (麩胺酸運輸蛋白)被發現分別在微管乙醯基化程度上升與持平情況下降低UNC-104運動性。本研究因此試圖連結這三項因素(突觸傳遞、微管蛋白後轉譯修飾及軸突運輸)。我們首先揭露以藥物抑制乙醯膽鹼突觸傳遞與過表達乙醯轉移酶MEC-17降低了UNC-104移動速度與總移動距離。乙醯膽鹼突觸傳遞抑制劑levamisole與MEC-17過表達皆減少了分子馬達的方向轉換。我們不但再次確認了在unc-17(e245)與eat-4(ky5)中降低的UNC-104運動性，也透過增加的分子馬達持續性移動顯示了可能的微管蛋白後轉譯修飾變化。有趣的是，這項特徵亦能在levamisole處理與MEC-17過表達中發現。我們亦能單純藉由基因敲落MEC-17來拯救unc-17(e245)中觀察到的分子馬達移動性改變，然而過表現去乙醯酶HDA-6無法拯救該缺陷。我們展示了相較於乙醯轉移酶，基因敲落去乙醯酶在eat-4(ky5)中有更強的負面影響，且沒有觀察到任何拯救效果。此外在雙分子螢光互補試驗中，我們揭露了UNC-17、UNC-104和MEC-17在原位的交互作用。有趣的是，基因敲落MEC-17後，我們觀察到增強的UNC-17/UNC-104雙分子螢光互補對訊號。我們推測透過這些蛋白的直接連結，乙醯膽鹼突觸傳遞得以調節微管乙醯基化，而乙醯基化程度的改變進一步介導UNC-104軸突運輸。

The relation between axonal transport and neurological diseases has been thoroughly studied. UNC-104/KIF1A is the major transporter of synaptic vesicles in neurons and defects in this motor has been related to Charcot-Marie Tooth diseases as well as Hereditary spastic paraplegia (HSP). In a previous Master thesis from our lab (Zaira Wang, 王孟婕), two synaptic defect strain unc-17(e245) (ACh transporter) and eat-4(ky5) (L-glutamate transporter) have been identified to reduce UNC-104 motility with microtubule acetylation increased and unaltered, respectively. The study now attempts to tie these three factors together (synaptic transmission, posttranslational modification of tubulin, and axonal transport). We first showed reduced UNC-104 velocity and total run length with drugs specifically inhibiting ACh neurotransmission and overexpressing acetyltransferase MEC-17. ACh neurotransmission inhibitor levamisole and MEC-17 overexpression both reduced directional changes of motor. We not only confirmed the diminished UNC-104 motility in unc-17(e245) and eat-4(ky5) but also showed possible changes in tubulin PTMs with increased motor persistent moving. Interestingly, this characteristic was observed in levamisole treatment and MEC-17 overexpression as well. We were also able to rescue observed changes in motor movements in unc-17(e245) by simply knockdown of MEC-17; however, overexpressing deacetylase HDA-6 could not rescue the defect. We showed that knockdown of deacetylase had a stronger negative effect in eat-4(ky5) as compared to acetyltransferase, and no rescue effect was observed. Furthermore, in BiFC assays, in situ interaction between UNC-17, UNC-104, and MEC-17 were revealed. Interestingly, for UNC-17/UNC-104 BiFC pair, we observed increased signal after mec-17 knockdown. We speculate that through direct link between three proteins, ACh neurotransmission could regulate tubulin acetylation, and the change in acetylation level then mediate UNC-104 axonal transport.

Acknowledgments...i
摘要...ii
Abstract...iii
1 Introduction...1
1.1 Axonal transport and synaptic transmission...1
1.1.1 Overview of axonal transport and synaptic transmission..1
1.1.2 Acetylcholine neurotransmission...2
1.1.3 Glutamate neurotransmission...3
1.2 Posttranslational modifications (PTMs) of tubulin...3
1.2.1 Overview of PTMs on tubulin...3
1.2.2 Acetylation of tubulin...4
1.3 Synaptic defect and tubulin acetylation – previous work...5
1.4 Specific aim of the study...6
2 Materials and Methods...8
2.1 Worm maintenance and reagents...8
2.1.1 Nematode growth media (NGM) agar plates...8
2.1.2 M9 Buffer...8
2.1.3 LB medium...8
2.1.4 Genomic DNA isolation buffer...8
2.1.5 NGM plates to induce ACh transmission defects...9
2.2 Plasmid construct...9
2.3 C. elegans strains...10
2.4 Crossing...11
2.5 Microinjection...12
2.6 RNAi by feeding...13
2.7 Paralyzing C. elegans by drugs...13
2.8 Motility analysis...14
2.9 Colocalization analysis...14
2.10 Fluorescence intensity quantification...15
2.11 BiFC assays...15
2.12 Statistical analysis...15
3 Results...16
3.1 Generation of new transgenic lines expressing UNC-104::mRFP..16
3.2 Effects of neurotransmission disruption and MEC-17/UNC-17
overexpression on UNC-104 motility...16
3.2.1 Levamisole and aldicarb disturb the motility of UNC-104 in ALM neurons...17
3.2.2 Overexpressing MEC-17 in wild type worms disturbs the motility of UNC-104 in ALM neurons...18
3.2.3 Synaptic defect strains reveal reduced anterograde and retrograde velocity of UNC-104...19
3.3 Effects of acetyltransferase and deacetylase expression on UNC-104 motility in worms with an ACh transporter mutation (unc-17)...20
3.3.1 Mec-17 knockdown significantly rescues reduced microtubule
acetylation in unc-17(e245)...21
3.3.2 Knocking down two different deacetylases do not rescue observed unc-17(e245) effects on motor motility...22
3.4 Changes of acetyltransferase and deacetylase expressions have only a minor effect on UNC-104 motility in eat-4(ky5) mutants...23
3.5 Colocalization between UNC-104 and UNC-17 significantly changes
after knocking down genes affecting tubulin acetylation...24
3.6 BiFC assays reveal in situ interactions between UNC-17, UNC-104 and MEC-17...24
4 Discussion...26
4.1 Disrupted ACh synaptic transmission leads to reduced axonal transport...26
4.2 Microtubule acetylation affects kinesin-3 UNC-104/KIF1A motility...28
4.3 ACh neurotransmission may mediate microtubule acetylation level to regulate UNC-104/KIF1A based transport...32
4.4 Future outlook...34
5 References...36
6 Figures...43
Appendix...60

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