Mechanism of cerebellar neuronal cell death in CTX patients

CTX是一种以高胆固醇血症、小脑性共济失调、跟腱黄瘤、白内障和过早动脉粥样硬化为特征的遗传性脂肪堆积性疾病。小脑性共济失调和白内障的病因尚不清楚。为了阐明小脑性共济失调和白内障的病因，我们建立了环磷酰胺喂养的大鼠模型。经组织化学分析，胆甾醇沉积在晶状体、角膜和小脑中。因此，我们推测胆甾醇可能诱导包括浦肯野细胞、角膜内皮细胞和晶状体上皮细胞在内的小脑神经元细胞的凋亡。对这些细胞进行原代培养，并在培养液中加入胆甾醇。TUNEL法检测胆甾醇诱导的细胞凋亡，半胱氨酸天冬氨酸氨基转移酶的诱导，以及细胞形态的改变。本研究结果可能解释环磷酰胺患者小脑性共济失调和白内障的发病机制。

CTX is a hereditary lipid storage disease characterized by hypercholestanolemia, cerebellar ataxia, Achilles tendon xanthoma, cataract, and premature atherosclerosis. The etiology of cerebellar ataxia and cataract is unknown. To clarify the etiology of cerebellar ataxia and cataract, we established model rats for CTX fed diets containing cholestanol. By histochemical analysis cholestanol was deposited in lens, cornea, and cerebellum. Therefore, we hypothesized that cholestanol may induce apoptosis of cerebellar neuronal cells including Purkinje cells, corneal endothelial cells, and lens epithelial cells. Primary culture of these cells were performed and cholestanol was added into culture media. Cholestanol induced apoptosis of these cells as judged by TUNEL method, induction of caspases, and morphological changes of these cells. The results in the present study may explain the mechanism of cerebellar ataxia and cataract in CTX patients.