摘要
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。
並列摘要
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.