2013-11-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/657707摘要：隨著近年台灣快速邁入高齡社會，神經退化疾病(如巴金森氏症及阿茲海默症等)的 預防及治療已成為不可輕 忽之問題。蛋白質降解以及傳送缺陷 (Intracellular sorting and degradation defects)是許多神經退化症神經元之共同病灶。儘管已 知神經元對細胞內的毒物堆積（neurotoxic accumulations）特別敏感，然而之前 均認為神經元與其他細胞內的蛋白質降解機制大致相同。近年研究顯示神經確具專 屬的降解機轉(neuron-specific sort-and-degrade machinery)；因此我的研究重 點在神經特有之胞內膜運輸機轉 (neuron-specific membrane trafficking mechanisms)如何調控蛋白質的降解，及其在人類神經疾病所扮演之角色。為了系 統性研究細胞內膜運輸如何調節神經退化，我的研究對象為胞內膜運輸的主要調節 者:the rab GTPases family。先前研究顯示 rab 及其調節者的基因突變會造成眾多遺傳性神經疾病；例如 rab7 突變造成 Charcot-Marie-Tooth type 2B disease， rab3 的活化蛋白突變造成 Warburg Micro Syndrome，以及 RabGDI (a Rab GTP dissociation inhibitor)突變造成 X-linked mental retardation 等等。我之前 利用果蠅為模式動物發現了神經細胞特有的五個 Rab GTPases；它們與 Rab11 在細胞內 colocalize (Rab11-positive intracellular compartments)。前人研究顯 示 Rab11 經由未知機制保護細胞(neuroprotective)抵抗 neurotoxic insults；因 此我們要探索這些新的 Rab GTPases 的保護能力，以及釐清其保護機轉。我將利用 果蠅及老鼠之神經系統，探討神經特有 Rab GTPases 對神經元退化之影響。此研究 盼能釐清細胞內蛋白堆積與神經蛋白降解在神經退化疾病的生理病理機轉。<br> Abstract: Neurodegenerative diseases have become serious medical problems in Taiwan, as the aging population expands rapidly. High prevalence, lack of effective treatment, and the lack of knowledge about the pathogenesis are the main obstacles in controlling neurodegenerative diseases. Intracellular sorting and degradation defects are hallmarks of numerous neurodegenerative diseases. Despite the apparent susceptibility of neurons in particular, the intracellular degradation machinery is thought to be principally shared with other cell types and there was until recently little evidence for a dedicated neuronal degradation mechanism. Recent research indicates neuron-specific intracellular trafficking mechanisms exist and may be critical to neurodegenerative diseases. To systematically investigate how neurodegenerative diseases are regulated by intracellular trafficking, I decided to tackle the rab GTPases family, which is regarded as the master regulators of the intracellular membrane trafficking. The importance of Rab function in the nervous system is furthermore highlighted by the observation that mutations in rab genes and their regulators cause several hereditary and neurological diseases including Griscelli syndrome (Rab27), Charcot-Marie-Tooth type 2B disease (Rab7), Warburg Micro Syndrome (a GTPase activating protein for Rab3), X-linked mental retardation (RabGDI – a Rab GTP dissociation inhibitor) and Hermansky-Pudlak syndrome (a Rab geranylgeranyl transferase). Using Drosophila as a genetic model organism, I have established a medium throughput platform to facilitate the systematic knockout and functional profiling in complete gene families. The systematic profiling studies that I performed have revealed six novel neuron-specific Rab GTPases that colocalize with potential neuroprotective Rab11-positive intracellular compartments. Motivated by these discoveries, I propose to investigate neuron- specific membrane trafficking mechanisms that function in intracellular degradation and their role in human disease models. I will systematically explore the role of all neuron-specific Rab GTPases identified in a profiling effort in flies in both Drosophila photoreceptors and mouse neuronal culture for their role in neuronal maintenance/degradation. Through these studies I seek to contribute to answering key questions of the relationship between intracellular accumulations, neuronal degradation machinery and neurodegenerative pathology.