小腦萎縮症第十七型 (Spinocerebellar ataxia type 17, SCA17) 是一種漸進式的體染色體顯性神經退化性遺傳疾病，由轉錄因子TBP (TATA-box Binding Protein) 基因上的CAG三核苷擴增所引起。在臨床上，SCA17的病人會表現出運動失調、張力障礙、震顫性麻痺、癡呆、局部痙攣等症狀。此外，在SCA17的病人及我們所使用的SCA17基因轉殖小鼠上，小腦皮層中負責統和感覺及運動訊息的Purkinje cell，均有死亡、缺損的現象。當Purkinje cell發生死亡，小腦的功能便會受到影響。Valproic acid (VPA) 是一種短鏈脂肪酸類的組蛋白去乙醯酶抑制劑 (histone deacetylase inhibitor, HDACi)，可以透過抑制GABA轉氨酶(GABA transaminase) 的活性，提升腦內GABA的濃度。透過疾病小鼠模式，VPA已經被證實對於許多神經退化性疾病有治療的效果，例如肌萎縮性脊髓側索硬化症 (amyotrophic lateral sclerosis, ALS) 及脊髓性肌肉萎縮症 (spinal muscular atrophy, SMA)。而透過細胞模式的研究，VPA被證實可以減低多麩醯胺酸 (polyglutamine, polyQ) 對神經細胞所造成的毒性。本研究利用運動失調症狀及Purkinje cell缺損現象已被確認的SCA17基因轉殖小鼠，自四週齡起，透過日常飲水給予0.26% w/v 濃度的VPA；透過Rotarod測試，投藥後的SCA17小鼠在運動協調能力上有顯著的進步；而透過免疫化學染色及免疫螢光染色技術，我們也發現投藥後SCA17小鼠的Purkinje cell有較高的存活率及較正常的形態。綜合以上結果，我們認為VPA是一具有治療SCA17的潛力藥物。

Spinocerebellar ataxia type 17 (SCA17), an autosomal dominant and progressive neurodegenerative disease, is caused by a CAG repeat expansion in the gene encoding transcription factor TBP. Several clinical symptoms, such as ataxia, dystonia, parkinsonism, dementia and seizures could be identified in SCA17 patients. Furthermore, loss of cerebellar Purkinje cells could be found in both SCA17 patients and our SCA17 transgenic mice. Purkinje cells are a class of GABAergic neuron located in the cerebellar cortex, which are fundamental for integration of sensory and motor information in motor coordination. Once the Purkinje cells died, the function of cerebellum would be affected. Valproic acid (VPA), a short chain fatty acids histone deacetylase inhibitor (HDACi) compound which can raise the concentration of GABA in the brain by inhibit GABA transaminase activity, 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 also showed that VPA can reduce polyglutamine (polyQ) toxicity and protect neurons. In this study, SCA17 transgenic mouse model, whose ataxia phenotype and Purkinje cell lose has been confirmed, were treated with 0.26% w/v VPA in daily drinking water from the age of 4 weeks. The rotarod task analyses have shown a significant improvement in motor coordination in transgenic mice after treated with VPA, and the neuronal protection effect on Purkinje cell survival and cell morphology were also identified by immunohistochemical and immunofluorence staining. These results reveal that VPA could be a potential compound for SCA17 therapy. The molecular mechanisms of VPA effect on SCA17 mouse model will be further investigated and should uncover more information in SCA17 pathogenesis.

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