脊髓小腦萎縮症(Spinocerebellar ataxia)是一種體染色體顯性遺傳的神經退化疾病，各型脊髓小腦萎縮症在臨床病徵與基因表現程度上具有異質性，但主要病徵皆為小腦遭受損害。Valproic acid (VPA)為一臨床上沿用已久之抗癲癇藥物，具有穩定神經功能，近年來開始被應用在神經退化性疾病模式研究。2004年Sugai等人以腹腔注射方式在漸凍症 (Amyotrophic lateral sclerosis) 疾病模式小鼠做VPA投予，結果顯示VPA具有延緩疾病發生的年齡效果；2006年Tsai等人給予脊髓性肌肉萎縮症 (Spinal muscular atrophy) 模式小鼠VPA之後，原本退化的運動神經有復原的現象；另外經由細胞實驗也發現，VPA具有減緩多麩醯胺不正常擴增對細胞造成之毒性以及抑制細胞死亡。基於以上文獻報導，我們希望能了解VPA在同樣屬於多麩醯氨所引起的脊髓小腦萎縮症之不同型動物及細胞上是否也具有延緩細胞死亡以及降低多麩醯胺對細胞產生毒性的功效。以實驗室已經建立好具有明顯病徵以及小腦Purkinje細胞嚴重受損的SCA第十七型 (SCA17) 轉殖鼠進行為期13週0.26%重量百分濃度的VPA投予，結果顯示在滾輪測試行為表現上，VPA投予與否並沒有顯著改善小鼠運動能力；但是在組織免疫染色切片結果比較之下，VPA的投予明顯具有保護Purkinje細胞，延緩Purkinje細胞退化的功能。此外，我們以大鼠腎上腺嗜鉻細胞株建立SCA第三型 (SCA3) 誘導蛋白表現系統，利用昆蟲褪皮激素相似化合物(Ponasterone A)在細胞內誘導含有不同長度多麩醯胺片段的AT3蛋白，此系統成功建立之後可供未來VPA以及其他候選藥物之療效與機制探討使用。利用目前已建立之誘導性SCA3細胞模式以及SCA17轉殖小鼠模式，可更進一步探討VPA在脊髓小腦萎縮症的治療機制，並且提供已有藥物甚至是新開發藥物篩選的體外與體內平台。

Autosomal dominant spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders primarily affecting the cerebellum. Valproic acid (VPA) has been reported as an effective molecule in neurodegenerative disease models such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) mouse models. In vitro studies have also shown that VPA can reduce polyglutamine (polyQ) toxicity and suppress neuron death. Considering these studies, it is possible to ameliorate symptoms of polyQ-mediated SCAs through VPA treatment. In this study, we use two systems to test this possibility. First, our SCA17 transgenic mice, whose ataxia phenotype and Purkinje cell lose have been confirmed, were treated with 0.26% w/v VPA for 13 weeks. No significant improvement in behavior was identified in these animals; however, immunohistochemical analysis shows that Purkinje cell morphology of VPA treated mice is better protected than those non-treated animals. In addition, SCA3 ecdysone regulatory inducible system in PC12 cells have been established and will be used to test VPA effectiveness in vitro. With both SCA17 in vivo and SCA3 in vitro systems, we should be able to evaluate whether VPA can ameliorate the polyQ toxicity in a common mechanism. Results obtained from this study should provide more information for therapeutic strategy designing in the future clinical application and reveal more implication about the molecular mechanisms of polyQ-mediated neurodegenerative diseases.

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