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研究生:黃子庭
研究生(外文):Tzu-Ting Huang
論文名稱:線蟲感覺神經系統老化的探討
論文名稱(外文):Aging of the sensory nervous system in C. elegans
指導教授:潘俊良潘俊良引用關係
指導教授(外文):Chun-Liang Pan
口試委員:謝松蒼歐展言
口試委員(外文):Sung-Tsang HsiehChan-Yen Ou
口試日期:2016-07-15
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:分子醫學研究所
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:2016
畢業學年度:104
語文別:英文
論文頁數:95
中文關鍵詞:線蟲感覺神經感覺神經纖毛老化神經功能及神經構造
外文關鍵詞:C. elegansagingsensory neuronsheath cellcilia
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老化是許多退化性神經病變的主要風險因子,而感覺神經系統的老化可導致感知功能低下甚至永久性的功能喪失。為了瞭解感覺神經系統老化的機制,本研究藉由探討感覺神經系統主要偵測外界刺激並傳遞訊號至下游迴路的特化構造─感覺神經纖毛(sensory cilia)在老化過程中結構及功能的變化,進而闡述調控神經老化的基因機制。本實驗室先前曾發表線蟲觸覺神經元(touch mechanosensory neuron)老化的特徵;在此,我們在線蟲多種感覺神經纖毛中皆觀察到老化相關的結構異常:老化時,溫感神經元AFD末梢的微纖毛(microvilli)數量明顯減少,嗅覺神經元AWB的纖毛異常膨大,而AWC嗅覺神經纖毛則明顯萎縮味覺神經元ASE及化學神經元ASI纖毛周邊膜狀結構則異常腫大。此外,線蟲對溫度的趨向行為也隨著老化而變差,顯示著老化造成的感覺纖毛異常可能導致感覺功能的喪失。本研究也發現維持AFD、AWB及AWC神經纖毛功能及發育的神經鞘細胞(sheath cell)結構有老化的趨勢,而過度表現TAX-4陽離子通道或剔除GCY-8受器型鳥苷酸環化酶可改善AFD神經纖毛結構的老化,暗示神經活性及神經鞘細胞有助於維護神經纖毛老化過程中的結構穩定性。綜合以上發現,本研究描述多種感覺神經纖毛老化的特徵及溫度趨向性功能之衰退,這些神經纖毛結構的老化可能為感覺神經系統最早出現的老化徵兆,本研究也歸納出可能導致感覺神經功能老化的機制:神經活性的降低、膜狀胞器運輸系統的異常及神經鞘細胞的老化等。神經纖毛結構在不同物種間的高度共通性,暗示本研究應用於探討哺乳類神經系統老化的可行性,有助於從老化機制開拓預防或治療退化性神經病變的新策略。

Microtubule-based sensory cilia are unique signaling compartments in the sensory neurons that transform environmental cues into sensory perception. Deterioration in sensory function is a common manifestation of aging. To provide a detailed description of ciliary morphology during neuronal aging, we focus on C. elegans amphid sensory neurons. Consistent with our previous findings in aging mechanosensory neurons, we find widespread morphological changes in multiple classes of sensory cilia in the amphid, including reduced microvilli and engorged cilia in the AFD thermosensory neuron, distorted cilia in the AWB and AWC olfactory neurons, and enlarged periciliary membrane compartments in the ASE and ASI chemosensory neurons. Aging of the AFD endings is associated with deterioration in thermosensory behaviors. Insterestingly, we observe age-related defects in the amphid sheath cells, glial cells that ensheath the AFD, AWB and AWC neurons. Overexpression of the TAX-4 cation channel or elimination of the GCY-8 receptor type guanylyl cyclase ameliorate age-dependent defects of the AFD sensory endings, suggesting that neuronal activity and glial influence contribute to the maintenance of sensory endings during aging. Taken together, our observations indicate that C. elegans sensory cilia undergo age-dependent deterioration in morphology and functions, which may represent one of the earliest aging signs of the sensory neurons.

國立台灣大學碩士學位論文口試委員審定書 i
ACKNOWLEDGEMENT iii
中文摘要 vii
Abstract ix
CONTENTS xi
Chapter 1 INTRODUCTION 1
1.1 C. elegans Amphid Sensory Neurons 3
1.2 Structure and Functions of Sensory Cilia in C. elegans 5
1.3 Genes and Signaling Pathways That Regulate Ciliary Development and Functions in C. elegans 6
1.4 The role of amphid glia in supporting ciliary structure and function 8
1.5 Age-Dependent Changes of Ciliary Structures 10
Chapter 2 MATERIALS and METHODS 13
Chapter 3 RESULTS 17
3.1 Nerve Ending of AFD Thermosensory Neuron Showed Progressive Defects During Aging 17
3.2 Longevity Mutations Altered AFD Microvilli Structure in Accordance with Life Span Changes 18
3.3 Sensory Ending Defects Are Widespread in Multiple Classes of C. elegans Amphid Sensory Neurons 20
3.4 Preliminary Molecular Characterization of the Periciliary Membrane Compartment in Aging 22
3.5 Upregulation of the Cyclic Nucleotide-Gated Ion Channel TAX-4 Protects AFD Nerve Ending during Aging 22
3.6 Localization of Intraflagellar Transport Proteins During Aging 24
3.7 Deteriorated Isothermal Tracking Behaviors in Aged Animals 25
3.8 Morphological Changes of the Amphid Sheath Cell During Aging 26
3.9 Loss of GCY-8 guanylyl cyclase is protective for aging 28
Chapter 4 DISCUSSION 29
4.1 The Genetic Basis of Ciliary Aging 29
4.2 Degenerated Cilia as One Structural Basis for Age-Dependent Behavioral Defects in C. elegans 31
4.3 The Role of Glia Cells in Age-Dependent Defects of the Sensory Endings 33
Chapter 5 FIGURES 35
Figure 1. The six pairs of sensory organs in C. elegans 36
Figure 2. The Structure and Intraflagellar Transport of C. elegans cilia 38
Figure 3. Receptive Nerve Endings of the AFD Thermosensory Neuron 40
Figure 4. Age-Dependent Defects of the Receptive Nerve Endings of the AFD Neuron 42
Figure 5. Age-Dependent Defects of the AFD Dendrite 44
Figure 6. Correlation between Dendrite and Sensory Ending Defects in the Aging AFD Neuron 46
Figure 7. Longevity Mutations Alter the Progression of AFD Aging in Accordance with Life Span Changes 48
Figure 8. Age-Dependent Morphological Changes in the AWB and AWC Olfactory Neurons 50
Figure 9. Progressive Enlargement of the PCMC in the ASI Chemosensory Neuron during Aging 52
Figure 10. Progressive Enlargement of the PCMC in the Aging ASE Gustatory Neuron 54
Figure 11. Labeling of the Periciliary Membrane Compartment with Endocytic Markers 56
Figure 12. Localization of Endocytic Proteins in the AFD Dendrite and Soma 58
Figure 13. Localization of the Cyclic Nucleotide-Gated Ion Channel TAX-4 in the AFD Sensory Ending 60
Figure 14. Localization of the Intraflagellar Transport Protein OSM-6 during Aging 62
Figure 15. Isothermal Tracking Behavior 64
Figure 16. Isothermal Tracking Behaviors of the Young Wild-Type Animals 66
Figure 17. Isothermal Tracking Behaviors in Aged Wild-Type Animals 68
Figure 18. Morphological Changes of the Amphid Sheath Cell during Aging 70
Figure 19. Association of the AFD, AWB and AWC Neurons with the AMsh cell 72
Figure 20. Age-related Changes of AFD Sensory Endings in GCY-8 mutant 74
Figure 21. Schematic Model of Aging of Ciliated Nerve Endings in C. elegans 76
Chapter 6 SUPPLEMENTARY TABLES 79
Table 1. Statistics of AFD Sensory Ending 80
Table 1. Statistics of AFD Sensory Ending (Continued) 81
Chapter 7 REFERENCE 83

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