Machado-Joseph 疾病是晚發性的體染色體顯性遺傳性疾病，一種小腦脊髓漸進性神經退化性疾病，此疾病的徵狀在林床上變化很多，顯現範圍很廣，主要病徵有：運動失調、漸進性眼外肌麻痺、錐體及外錐體路徑的病徵、肌張力的異常及僵硬末梢肌萎縮、臉部及舌的顫搐。MJD 的基因位於在第14對染色體長臂上，在靠近3'端轉譯區(translated region) 內，有一段不穩定的CAG核酸重複序列倍增突變有關。有關 MJD 疾病的治療至目前為止仍根據臨床徵狀來治療，Lamotrigine 是一種新的抗癲癇藥物，被廣泛用來治療單純性或複合性的痙攣。根據臨床的觀察發現Lamotrigine 能夠減輕 MJD 臨床的症狀，因此我們藉由培養含有 MJD 蛋白的淋巴母細胞來處理 lamotrigine 後，觀察蛋白的表現變化。 建立淋巴母細胞株，其中含有已發病、未發病之成員及正常人，細胞來處理 lamotrigine 後，以西方轉漬法分析 MJD 蛋白表現。在未加入 lamotrigine 處理前，在已發病、未發病的 MJD 蛋白表現並無差異，而加藥物處理後發現 lamotrigine 的濃度由 50 μΜ增加到 300μΜ時，會降低 MJD 蛋白的表現，顯示 lamotrigine 對 MJD 蛋白的表現有劑量相關性。這個結果與臨床觀察的現象相似，希望能夠更清楚了解 lamotrigine 對 MJD 的治療所扮演的角色及對 MJD 的致病機轉的研究有所幫助。 We have investigated in the present study the effect of lamotrigine (LTG) on the Machado-Joseph disease protein (ataxin-3) in cultured lymphoblastiod cells. Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration characterized by a wide range of clinical manifestations, including ataxia, progressive external opthalmoplegia, pyramidal and extrapyramidal signs, dystonia with rigidity, and distal muscular atrophies. Unstable CAG trinucleotide repeat expansion in MJJ gene on long arm of chromosome 14 has been identified as the pathologic mutation of MJD . The treatment of MJD has so far been purely symptomatic. Lamotrigine, an antiepileptic drug, was found to specifically relieve some major symptoms of MJD patients. Encouraged by the clinical observation, we carried out the molecular basis for this observation.’ Lymphoblastiod cell lines (LCLs) from patients, at-risk individuals, and normal control were established. Western blot analysis was then performed to study the expression of ataxin-3 protein in cultured cells under the treatment of LTG. Even though the ataxin-3 protein levels show no observed differences among patients’and at-risk individuals’LCLs before drug treatment, our results demonstrated that the LTG-treated MJD cells express less mutant ataxin-3 proteins. Extracellular application of LTG (50 to 300μΜ) decreased the expression of mutant ataxin-3 protein in a dose-related manner. This observation is consistent with the clinical phenomena. Further analysis is underway for better understanding of the role(s) which lamotrigine may play in the pathogenesis MJD.
