探討rab27於果蠅腦中對壽命調節、能量平衡、神經肽運輸之神經迴路及作用機制

Abstract

在果蠅及哺乳類動中，我們能夠操控中樞神經系統訊息來調節壽命。我的研究中發現特別表現在某部分神經細胞之rab27，其剔除後導致壽命延長，而表現Rab27-PB則會抑制壽命延長，顯示Rab27-PB扮演主要調控壽命之角色。過去對於壽命調控之研究，主要聚焦於腦中胰島素分泌細胞所調控之胰島素訊息，胰島素分泌細胞與人類胰臟β細胞功能相同。而掌管學習記憶之蕈狀體與壽命延長的關係則少被提及。在我們實驗結果中，於蕈狀體及GABA receptor細胞抑制rab27表現造成壽命延長，顯示Rab27主要作用位置為蕈狀體的GABA receptor細胞。過去文獻指出於腦中減少TOR訊息導致壽命延長，我們在剔除rab27果蠅中表現S6KDN，其壽命並沒有比rab27剔除果蠅更加延長，表示Rab27可能經由TOR訊息調控壽命。先前文獻指出Rab27主要於神經內分泌細胞中調控胞吐作用，因此我們提出Rab27可以控制某種神經肽分泌，因而延長壽命之假說。及時聚合酶鏈式反應結果顯示，果蠅的細胞激素upaired2 (upd2) 在失去rab27組別有顯著增加。另外在rab27表現細胞大量表現Upd2，發現壽命延長，但是在失去rab27情況下同時在rab27表現細胞中大量表現Upd2，卻沒有看到壽命更加延長之加成現象，此結果暗示失去rab27延長壽命是經由Upd2所造成。我的研究了解壽命調控之新的神經迴路及訊息傳遞: 經由Rab27於蕈狀體中調控，並藉由抑制TOR訊息及調節神經肽之運輸而延長壽命。

Central nervous system controls lifespan in mammals and Drosophila. Recently we have discovered a novel function of neuronal specific Rab27 in lifespan regulation, and expression of Rab27-PB, Rab27 PB isoform in rab27KO flies fully suppressed the enhanced lifespan back to WT, indicating that the longevity controlled by Rab27-PB. Amples of literatures demonstrate that insulin/IGF signaling (IIS) from the median neurosecretory cells (mNSCs), the functional homolog of the mammalian pancreatic β cells, plays an important role in lifespan regulation in the brain. In contrast, little is reported on the lifespan regulation by the mushroom body (MB), the information integration center important for diverse behavioral functions including learning and memory. Our neuronal circuitry mapping shows that loss of rab27 specifically in MB and GABAergic receptor-expression cells leads to extended lifespan. It has been shown that reduced TOR signaling in the brain results in lifespan extension. Our data show that expressing the dominant negative form of S6 kinase (UAS-S6KDN) in rab27KO background does not further extend the enhanced lifespan by the single mutant rab27KO, suggesting that Rab27 may act through TOR pathway in regulating lifespan. Since Rab27 is a “secretory rab” that regulates exocytosis in neuroendocrine cells, thus we hypothesize that Rab27 may controls the secretion of a specific neuropeptide for lifespan extension. The RT-PCR data of the candidate genes in rab27KO brain indicate that the mRNA level of Drosophila cytokine unpaired2 (upd2) is increased in rab27KO. Lifespan result show that while expressing UAS-upd2 by rab27-Gal4 in the wild type background increases the longevity, expressing UAS-upd2 in rab27KO background does not display further extension. This result indicates that upd2 may genetically interact with rab27. Together, identify the neuronal circuit and signal transduction of novel longevity pathway: loss of rab27 in mushroom body reduces TOR signaling and extends lifespan. Rab27 also control Upd2 trafficking to extend lifespan.