探討芹菜素對第三型小腦脊髓運動失調症的神經保護作用

第三型小腦脊髓運動失調症 Spinocerebellar ataxia type 3 (SCA3)，又稱為MachdoJoseph Disease (MJD)，屬於體染色體顯性遺傳疾病，病因是在Ataxin 3基因編碼中CAG不正常擴增造成多麩胺酸 (Polyglutamine, Poly Q)在細胞中堆積。目前對於致病機制仍不明確，但已知聚集的突變蛋白會產生神經毒素而引發氧化壓力的上升。本實驗架構主要探討具有豐富黃酮類化合物的芹菜素(Apigenin, API)，其在低劑量時可有效進行抗氧化作用，並對神經細胞具有保護作用且有效減緩神經退化性疾病。本實驗以API在不同濃度下培養，利用SK-N-SH-MJD78的細胞模型及MJDtr-Q78基因轉殖的果蠅動物模型進行實驗。結果顯示，API會啟動細胞自噬，使細胞內ROS及抗氧化蛋白表現量下降，且細胞預先處理API再以CQ誘導的自噬蛋白表現量也可減少細胞凋亡；在果蠅模型的存活率及運動能力皆有顯著改善。藉此證明API對於SCA3在細胞及動物模型具有抗凋亡和促進神經細胞存活來達到神經保護作用，API具有預防第三型小腦脊髓運動失調症的潛在治療藥物。

Spinocerebellar ataxia type 3 (SCA3) /Machado Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration characterized by a wide range of clinical manifestations. Unstable CAG trinucleotide repeat expansion in the SCA3 gene has been identified as the as a pathologic mutation of SCA3. Although the detail mechanism of pathogenesis is yet to be defined, neurotoxin, especially reactive oxygen species (ROS), release from aggregated mutant proteins, may play a role in the pathogenic process. Apigenin (API) is a flavonoid in a variety of natural sources, which has a variety of biological activities such as antioxidant and neuroprotective in low dose of API. In this experiment, we used different concentrations with API on SK-N-SH-MJD78 cells and MJDtr-Q78 Drosophila was studied. Pretreatment with 1.5 µM API significantly enhanced cell viability, reduced ROS levels, alleviated apoptosis, and up-regulated autophagy in SK-N-SH-MJD78 cells. In addition, API treatment in vivo significantly improved survival and locomotor activity in MJDtr-Q78 Drosophila. Our findings suggest that the neuroprotective potential of API in SCA3 in vitro or in vivo model. These results show that lowly concentration API may be a potential therapeutic candidate for neurodegenerative diseases involving glutamate cytotoxicity such as SCA3.