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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 潘俊良(Chun-Liang Pan) | |
dc.contributor.author | Hao-Ching Jiang | en |
dc.contributor.author | 姜浩菁 | zh_TW |
dc.date.accessioned | 2021-06-16T05:11:18Z | - |
dc.date.available | 2019-10-09 | |
dc.date.copyright | 2014-10-09 | |
dc.date.issued | 2014 | |
dc.date.submitted | 2014-08-18 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/55942 | - |
dc.description.abstract | 老化造成行為及認知上的衰退,並且伴隨著神經元結構以及功能的退化。Caenorhabditis elegans線蟲具有比哺乳動物相對較短的壽命並且是很好的基因體研究工具,我們實驗室利用線蟲作為實驗動物來研究神經老化的細胞分子機制。我們過去研究發現年老的線蟲觸覺神經會出現型態上的變化,而且也證明神經活性在老化的過程中對於維持正常神經元型態是很重要的。本篇研究發現觸覺神經裡被螢光標的的粒線體隨著老化逐漸變得破碎,因此粒線體型態的改變可以被視為神經老化的特徵。透過螢光蛋白標的,這些破碎的粒線體碎片廣泛地和溶小體重疊,暗示著神經老化促進粒線體自噬增加的可能性。內質網與粒線體之間的緊密聯繫對於脂質生合成、鈣離子平衡以及粒線體的動態平衡是重要的;但這兩個胞器之間的聯繫會在神經老化早期發生顯著的分離。hsf-1基因的突變會縮短線蟲的壽命,同時也會使粒線體的破碎提早發生;相反地,daf-2基因的突變會延長線蟲的壽命,並且會延緩粒線體發生碎裂。我們也證明了上皮鈉離子通道/退化蛋白 (epithelial sodium channel/degenerin, ENaC/Deg)的家族成員mec-4基因,以及電壓門控性鈣離子通道(voltage-gated calcium channel)的編碼基因egl-19對於維持觸覺神經裡粒線體型態的完整是重要的,因為在這兩種基因突變的情況下都會增加粒線體在老化過程發生碎裂的機率,而且它們是作用在同一條途徑來調控粒線體的型態。另外,在鈣離子/鈣調素依賴性蛋白激酶白激酶(CaMKII)的基因unc-43突變也看到粒線體在老化過程中提早發生碎裂的情形,類似其在mec-4和egl-19突變裡看到的表現,暗示unc-43作用在神經去極化的下游。然而,粒線體分裂蛋白基因drp-1被移除後可以抑制因為失去神經活性而造成的過度粒線體碎裂。在本篇研究中我們發現神經活性可以調控在老化過程中粒線體的型態。 | zh_TW |
dc.description.abstract | Age-dependent behavioral and cognitive decline is accompanied by structural and functional deterioration in senescent neurons. Modeling neuronal aging in the mammalian brain is hampered by the relatively long life span of the common lab mammals. Robust genetics and the short life span make Caenorhabditis elegans a promising model to investigate the molecular and cell biological basis of neuronal aging. In our previous study, we found that characteristic age-dependent defects occur in the C. elegans touch neurons, and sensory evoked activity is required to maintain neuronal integrity during aging. Here we report that progressive mitochondrial fragmentation is a hallmark of touch neuron aging, and that sensory evoked activity is required for a balanced mitochondrial dynamics in these neurons. Our FRAP analysis suggested that mitochondrial fragmentation documented with fluorescent probes did indicate physical disconnection of this organelle. Small mitochondrial fragments colocalized extensively with lysosomes, suggestive of age-dependent mitophagy in these neurons. Moreover, endoplasmic reticulum-mitochondria contact, which is critical for lipid synthesis, calcium homeostasis and mitochondrial dynamics, was lost early during aging. Mutations in hsf-1, which shorten C. elegans life span, markedly accelerated mitochondrial fragmentation in the touch neurons. A daf-2 mutation dramatically extended life span and also delayed mitochondrial fragmentation. Similar to axonal integrity in senescent touch neurons, maintenance of mitochondrial dynamics required sensory evoked activity. We showed that mutations in mec-4 and egl-19, which encode a Degenerin family sodium channel and a voltage-gated calcium channel, respectively, induced premature onset of mitochondrial fragmentation in the touch neurons, and the two genes acted in a common pathway. Mutations in the CaMKII gene unc-43 caused similar phenotypes, suggesting that CaMKII regulates mitochondrial morphology downstream of neuronal depolarization. Mitochondrial defects in neurons losing membrane activation could be suppressed by mutations in drp-1, which is a dynamin-related GTPase critical for mitochondrial fission. Togther this work uncovers mechanism by which neuronal activity regulates mitochondrial dynamics in aging touch neurons. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T05:11:18Z (GMT). No. of bitstreams: 1 ntu-103-R01448009-1.pdf: 1858209 bytes, checksum: c53e817ea87e0c1089ef0ac2afbfba42 (MD5) Previous issue date: 2014 | en |
dc.description.tableofcontents | Table of Contents
論文審定書 i Acknowledgement ii 中文摘要 iv ABSTRACT v Chapter 1 INTRODUCTION 1 1.1 Morphological Deteriorations in Aging Neurons 2 1.2 Mitochondria and Aging 3 1.3 ER-Mitochondria Contact 6 1.4 Neuronal activity and Mitochondrial Morphology 7 Chapter 2 MATERIALS AND METHODS 8 2.1 C. elegans Strains and Genetics 8 2.2 Transgenic Animals 9 2.3 Scoring of ALM and PLM Process Defects 9 2.4 Scoring of Mitochondrial Morphology 10 2.5 Fluorescence Recovery After Photobleaching (FRAP) 11 2.6 roGFP Imaging Analysis 12 Chapter 3 RESULTS 13 3.1 Mitochondria Showed Age-Dependent Fragmentation in C. elegans Neurons and Muscles 13 3.2 An Early Decline in Endoplasmic Reticulum-Mitochondria Contacts in Neuronal Aging 16 3.3 Fragmented Mitochondria Were Targeted to Lysosomes in Aged Touch Neurons 18 3.4 Longevity Mutations Altered the Progression of Mitochondrial Defects in Accordance with Life Span Changes 19 3.5 Neural Activity Maintains Mitochondrial Morphology during Neuronal Aging 20 3.6 Evoked Neural Activity Maintains Mitochondrial Morphology through the L-type Voltage-Gated Calcium Channel and Ca/Calmodulin-Dependent Kinase II 22 3.7 Evoked Neural Activity Maintains Mitochondrial Morphology by Inhibiting the Pro-Fisssion GTPase DRP-1 24 Chapter 4 DISCUSSION 27 4.1 Dissociation of Mitochondria and ER Occurs Early During C. elegans Neuronal Aging 27 4.2 Neural Activity Maintains Mitochondrial Morphology During Neuronal Aging 28 Chapter 5 FIGURES 32 Figure 1. Model of mitochondrial dynamics 32 Figure 2. Mitochondria associated with age-dependent neuronal defects in the processes of touch neurons. 34 Figure 3. Mitochondrial motility in the touch neuron process of old animals had no differences from that of young ones. 36 Figure 4. Mitochondrial in the touch neuron soma underwent progressive fragmentation 38 Figure 5. Mitochondrial in the thermosensory AFD neurons, and body wall muscles underwent progressive fragmentation 40 Figure 6. Mitochondrial morphology revealed by TOMM-20::mCherry correlated well with membrane connectivity 42 Figure 7. Fragmented mitochondria were more oxidized 44 Figure 8. ER-mitochondrial contact was lost early in aging neurons 46 Figure 9. Fragmented mitochondria colocalized with lysosomes in the touch neurons 48 Figure 10. Fragmented mitochondria did not colocalize with Golgi 50 Figure 11. Age-dependent mitochondrial fragmentation parallels life span changes. 52 Figure 12. Touch sensitivity decreased in aged animals. 54 Figure 13. Touch sensitivity mutants with altered touch neuron activation. 56 Figure 14. Neural activity maintains neuronal structures cell-autonomously. 58 Figure 15. Neural activity maintained mitochondrial morphology in the touch neurons. 60 Figure 16. VGCC maintained mitochondrial morphology in the touch neurons. 62 Figure 17. Neural activity maintained mitochondrial morphology through CaMKII. 64 Figure 18. Neural activity regulates ER-mitochondrial contact 66 Figure 19. Mutations in drp-1 suppressed excessive mitochondrial fragmentation in the mec-4 mutant. 68 Figure 20. DRP-1 levels in the touch neurons changed during aging. 70 Figure 21. GFP::DRP-1 localized to small mitochondria in the touch neurites. 72 Figure 22. Model of activity-dependent mitochondrial maintenance in the neurons. 74 Chapter 6 SUPPLEMENTARY TABLE 76 6.1 Age-dependent mitochondrial fragmentation in the WT and mutants 76 6.2 Age-dependent neuronal defects in WT and mutants 78 Chapter 7 REFERENCES 79 | |
dc.language.iso | en | |
dc.title | 線蟲神經系統粒線體型態在老化過程中的遺傳分析 | zh_TW |
dc.title | Genetic Analysis of Age-Dependent Mitochondrial Fragmentation in C. elegans neurons | en |
dc.type | Thesis | |
dc.date.schoolyear | 102-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 劉雅雯(Ya-Wen Liu),謝松蒼(Sung-Tsang Hsieh) | |
dc.subject.keyword | 線蟲,神經老化,神經活性,粒線體,內質網與粒線體的聯繫, | zh_TW |
dc.subject.keyword | C. elegans,neuronal aging,neural activity,mitochondria,ER-mitochondrial contacts, | en |
dc.relation.page | 82 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2014-08-19 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
顯示於系所單位: | 分子醫學研究所 |
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