哺乳類大腦中星狀膠質細胞是表現最多的膠質細胞種類，參與調控許多重要的功能，其中一項重要功能為透過其麩胺酸轉運蛋白(GLT-1)維持興奮性突觸神經傳遞物質麩胺酸濃度的恆定。若是星狀膠質細胞癌化則稱為神經膠質母細胞瘤，這種癌細胞在治療方面並沒有治癒辦法且預後能力較差，WHO 將此母細胞瘤歸類為第四級的癌症細胞，實驗室過去發表的文獻中提及人類膠質母細胞瘤A172 細胞株在抵抗外環境壓力時 BRCC3 表達量上升，幫助癌細胞對抗外在環境提升細胞生存能力，除此之外以病毒感染將 BRCC3 基因表現量降低時，細胞形態變得細長。在實驗前期，將 A172 細胞株 BRCC3 基因表現量降低，觀察對 A172 癌細胞的基因表達之影響。雖然，在過去研究當中已經證明 BRCC3 參與在細胞瘤的生長中，但是在 BRCC3 缺失狀態下膠質母細胞瘤細胞形態產生改變的原因仍然不清楚，在這實驗中，對 A172 細胞株的基因表現進行了定量及形態觀察，BRCC3是一種去泛素化酶參與細胞自噬進程同時也會參與DNA 修復，本實驗觀察細胞自噬後期的標誌物 LAMP1 蛋白，透過染色，可以發現細胞 BRCC3 表現量降低時會使其大量表現。另一方面，近十年來的文獻發現，精神疾病患者腦部環境常伴隨發炎現象發生。我們使用脂質混合物處理在體外模擬高脂飲食誘導之發炎環境，觀察含量高的脂質混合物處理導致星狀膠質細胞 GLT-1 基因表現降低。精神性疾病病患需要長期用藥，研究抗精神藥物是否會對星狀膠細胞基因表現有所影響是有其重要性的。鹽酸硫代利(TDZ)是其中典型的治療抗精神症狀的藥物，但是對於在發炎狀態下使用抗精神藥物 TDZ 對星狀膠質細胞的影響是不明確的；因此，實驗後期，探討經過 TDZ 處理是否會改變星狀膠質細胞功能性基因表現。研究在含有血清的培養環境，TDZ 不影響星狀膠細胞的存活率，但是顯著降低星狀膠細胞中天冬氨酸轉運蛋白(GLAST)與 BRCC3 基因的表現，而且星狀膠細胞的GLT-1 基因表現量也有下降趨勢。發炎物質刺激情況下，以發炎劑脂多醣(lipopolysaccharide；LPS)與 TDZ 共同處理，結果顯示單獨處理 TDZ 的星狀膠質細胞，在染色結果中細胞自噬標誌物 LC3 堆積，且有囊泡產生，此外在 LPS與 TDZ 共處理的組別中(TDZ/LPS)，同樣導致星狀膠質細胞中 LC3 堆積及明顯小囊泡的產生，此結果可以推測藥物 TDZ 能增加細胞自噬。這些實驗結果顯示在抗精神性藥物 TZD 會降低星狀膠細胞功能性基因的表現，並且誘發細胞自噬。
關鍵字: 星狀膠質細胞、BRCC3、GLT-1、細胞自噬、脂多醣

Altered astrocyte gene expression by lipid mixtures and anti-psychotic drug Thioridazine
Author: Guei-ren Liang
Advisor: Shun-Fen Tzeng
National Cheng Kung University Institute of life Sciences
Summary
Astrocytes are the abundant glia cells in mammalian brain, and function as the neuronal supporting cells. Astrocytes are involved in the maintenance of glutamate homeostasis at the excitatory synapse through astrocytic glutamate-aspartate-transporter (GLAST) and glutamate transporter-1 (GLT-1). Glioblastoma multiforme
(GBM), a grade four in WHO cancer classification which transformed from
astrocytes is the most common cancer cells in CNS brain tumors.
BRCA1/BRCA2-Containing Complex Subunit 3 (BRCC3) upregulation has been
known to increase cancer cell survival. Moreover, the research also shows
morphology changing in BRCC3-KD A172 cells. Accordingly, in this study we were
first to study the effect of BRCC3-KD in A172 cells. Although studies have already
showed their character in tumor cell growth, the changing morphology because the downregulation BRCC3 remains unknown. In our research, we analysis several gene expressions and recode the morphology in A172 cells. BRCC3, Lsy63
deubiquitinating enzyme, participate in cell autophagy regulation and DNA recovery as well. In addition, by immunofluorescence, we also observed that lysosome biomarker LAMP1 upregulated in BRCC3-KD A172 cells. On the other hand, in the recent years, inflammation can be observed in the brain of patients with psychiatric disorders. Using lipid mixtures to mimic the inflammatory environment induced by high-fat diet in vitro, we showed that the downregulation of GLT-1 was induced in astrocytes treated with a high amount of lipid mixtures. Given that patients with psychiatric disorders needs to take the anti-psychotic drugs for a long-term period, the effect of the drugs on the alteration of astrocytic gene expression is important to be uncovered. Thioridazine (TDZ) is a common anti-psychotic drug. Thus, we examined if exposure to TDZ altered astrocytic gene
expression. Exposure to TDZ did not affect the cell viability of astrocytes under
serum-containing culture condition, whereas TDZ can reduce GLAST and BRCC3
mRNA expression, as well as GLT-1 mRNA expression to some entent. We also
observed the clusters of microtubule-associated protein 1A/1B-light chain 3 (LC3)
in astrocytes exposed to either TDZ or inflammagen LPS combined with TDZ
(LPS/TDZ). Altogether, our findings indicate that exposure to TDZ caused the
downregulation of astrocytic functional gene expression and induced autophagy.
Key words: Astrocyte, BRCC3, GLT-1, autophagy, LPS

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