2012-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/643459摘要：神經系統的老化伴隨著神經元在結構和功能上的逐步退化。雖然多數生物的神經元數量在老化的過程中保持穩定，但其他隨著老化出現的細胞缺陷則相當明顯，包括突觸的減少、神經突起的退化，以及不溶性蛋白質的沉積。有許多基因已被證實和神經退化性疾病有關，但絕大多數調控神經系統生理性老化的基因則尚未被發現。近年來本實驗室以線蟲的觸覺神經元為主，建立了神經元老化的動物模式，用以探討神經系統老化的分子機制。在線蟲的觸覺神經元中，本實驗室發現數種老化的細胞結構變化，我們也證實這些老化相關的神經結構缺損受到類胰島素生長因子訊息路徑的調控。更重要的是，我們發現神經元的電氣活動，對於神經細胞在老化過程中維持結構的完整而言，扮演著不可或缺的角色。根據這些結果，本計畫將更進一步探討神經元老化的細胞生物學基礎，以及電氣活動如何維繫神經元結構的訊息傳遞路徑。我們將以溶小體、自噬體和粒線體為重點；因為過去的研究顯示，此二類胞器與線蟲的老化或人類的神經退化性疾病有密切的關聯。本實驗室將探究溶小體、自噬體和粒線體在老化過程中的形態與功能變化。我們也以基因突變或核醣核酸干擾的方式，進一步釐清它們在神經元老化中所扮演的角色。我們將探討電氣活動在維繫成體神經元的結構中的細胞作用位置，並進一步探究，在中年期時增強神經元的活動，是否能夠預防或逆轉神經細胞的老化症狀。我們假設，在電氣活動對神經元結構穩定度的調控作用中，鈣離子和cyclic AMP的濃度會升高。本實驗室將以一系列的基因突變，來改變透過離子通道進入細胞、或從內質網所釋放的鈣離子濃度。最後本實驗室將探索cyclic AMP訊息傳遞的改變對神經元老化的影響。本計畫的成果將有助於了解在老化過程中，有哪些重要的分子機轉負責維持神經元結構的完整性。因為老化是人類神經退化性疾病最重要的危險因子，這些成果將有助於開發更有效的治療方式，也可以為逐漸老化的國內人口開發改善神經系統功能的健康策略。<br> Abstract: Aging of the nervous system is characterized by progressive decline in neuronal structures and functions. While the numbers of neurons in most species are relatively preserved during aging, subcellular neuronal defects are evident in the senile nervous system, such as loss of synaptic structures, appearance of dystrophic neurites and accumulation of insoluble protein aggregates. Many genes had been implicated in the pathogenesis of neurodegenerative diseases; nevertheless, those involved in nervous system aging are largely unknown.To study the molecular genetic mechanisms underlying neuronal aging, we established a model of touch neuron senescence in the nematode Caenorhabditis elegans. We characterized several cytologic defects in aging C. elegans touch neurons, and showed that these age-dependent neuronal defects are regulated by highly conserved insulin signaling. Moreover, we identified electrical activity as a critical factor for neuronal maintenance during aging.Based on these observations, we propose to investigate the cellular basis of neuronal aging and the signaling pathways that mediate the effects of electrical activity on neuronal maintenance. We focus on lysosome, autophagosome and mitochondria, as these cellular compartments had been implicated in the regulation of general aging in C. elegans and pathogenesis of several human neurodegenerative diseases. We will study the age-dependent alterations of lysosomes, autophagosomes and mitochondria, and their roles in neuronal aging will be further investigated by genetic mutations or RNAi-mediated gene silencing. To understand how electrical activity contributes to the maintenance of adult neurons, we first investigate the cell autonomous requirement of electrical activity. We then address whether neuronal aging could be prevented or reversed by enhancing membrane activity during midlife. We hypothesize that increased levels of cytosolic calcium and cyclic AMP after membrane activation are required for the structural integrity of adult neurons. To test this model, we will modulate by genetic mutations the level of calcium influx through voltage-gated calcium channels or cytosolic calcium released from endoplasmic reticulum. We will also examine neuronal aging in animals with disrupted cAMP signaling. Progress in this project should further our current knowledge of the molecular mechanisms that maintain neuronal integrity during senescence. As aging is a critical factor that predisposes to common human neurodegenerative diseases, this research will also contribute to the development of strategies to treat these devastating disorders, or to improve nervous system functions in the aging population.神經退化老化線蟲neurodegenerationagingC elegans