SCA17為一種體染色體顯性遺傳之神經退化性疾病。目前已知SCA17致病原因與TBP基因之三核苷CAA/CAG重複序列擴增有關，正常族群之重複次數為25到42個，患病者則擴增為47到55個，一般推測三核苷重複不正常擴增所轉譯出之多麩醯胺可能影響到蛋白質結構的正確摺疊，使得蛋白質無法發揮其正常功能，最後導致細胞死亡。為了探討TBP蛋白Ｎ端多麩醯胺擴增與神經退化的關係，本研究室先前已利用基因轉殖小鼠技術，將含有109個CAA/CAG重複之人類TBP基因利用小腦Purkinje細胞專一性表現之Pcp2/L7啟動子建立SCA17之疾病動物模式，外觀及行為分析實驗發現，hTBP109Q小鼠有出現運動失調之症狀。本論文即進一步對小鼠腦部進行免疫組織化學染色分析，結果顯示基因轉殖小鼠小腦中的Purkinje cells 有明顯丟失之現象。進一步進行微陣列資料分析及西方墨點法確認後發現小腦中calbindin、inositol 1,4,5-triphosphate receptor 1 (Itpr1)及Cacna1g 表現量明顯降低，此結果指出hTBP 109Q在小鼠腦中可能造成鈣離子恆定上的失調，進一步造成細胞毒性增加、行為上的共濟失調及腦部的損傷；另外GFAP及Iba1表現量明顯增加，表示SCA17的小鼠腦部發生神經膠質細胞纖維化及神經發炎反應。我們進一步利用此SCA17小鼠作為藥物測試平台, 希望能提供更多SCA17致病分子機制及篩選具有治療性潛能藥物。本研究所選擇的藥物為granulocyte colony-stimulating factor (G-CSF)，我們發現，在SCA17小鼠發生症狀後施予G-CSF可以活化p-ERK存活相關的調控路徑，提供神經保護的作用。我們進一步針對發生症狀前的小鼠給予G-CSF，發現熱休克蛋白70表現量增加，病理上亦有所改善，可能藉由提升熱休克蛋白70的表現而達到神經保護的作用；另外，症狀前給藥也發現LC3-II/Actin的比值增加，表示細胞內自體吞噬作用活性提高，此現象增加SCA17蛋白的清除。我們的結論是不論於症狀前期或後期給予G-CSF 藥物皆有神經保護的效果，因此G-CSF對SCA17可能是一個具有潛力的藥物。

SCA17 is an autosomal dominant cerebellar ataxia (ADCA) caused by the polyglutamine (polyQ) expansion of transcription factor TATA binding protein (TBP). The length of polyQ tract encoded by the CAA/CAG repeats of TBP gene is related to the disease severity. The range of CAG repeats is 25-42 in normal population and 47-55 in SCA17 patients. We speculated that TBP trinucleotide expansion might disrupt comformation of protein folding and lead to cell death. To investigate the TBP trinucleotide expansion effect on neurodegeneration, our previous studies have generated transgenic (TG) mice expressing the human TBP (hTBP) gene with expanded 109 CAA/CAG tracts under the control of Purkinje cell-specific promoter, Pcp2/L7 promoter. These TG mice showed ataxia and reduced rotarod latency compared to their wild-type (WT) littermates. Immunohistochemical analysis has shown that the Purkinje cells in transgenic mouse cerebellum were lost severely. Furthermore, we confirmed that hTBP109Q TG mice had calbindin, inositol 1,4,5-triphosphate receptor 1 (Itpr1) and Cacna1g downregulated by both cDNA microarray and Western blot analysis. This result suggests that transgene expression in the mouse brain might result in the impairment of calcium homeostasis, which may in turn causes the neuron degeneration and ataxia. Reactive gliosis and neuroinflammation were also occurred in the TG mouse cerebellum showing the upregulation of GFAP and Iba1. The hTBP TG disease model recapitulates the phenotypes of SCA17 patients. This model could help us to gain more insight about the molecular pathogenesis and can be used as a platform for drug testing. We thus applied G-CSF on these mice to identify whether it could ameliorate the phenotypes of TG mice. Our results showed that G-CSF treatment at post-symptomatic stage could activate p-ERK survival pathway and showed neuroprotective effect on SCA17 transgenic mice. Compared to the late stage treatment, the G-CSF treatment at the pre-symptomatic stage showed increasing of Hsp70 expression level, which could retard the phenotype on the pathology and behavior of transgenic mice and result in a neuroprotective effect. G-CSF treatment of SCA17 mice also increased LC3-II/Actin ratio which suggested an increasing autophagy activity and enhanced the clearance of SCA17 protein. We conclude that at both the pre-symptomatic or post-symptomatic stages, G-CSF has neuroprotective effect on SCA17 mice. G-CSF may be a potential therapeutic drug for the treatment of SCA17 disease.

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