Mechanism of cerebellar neuronal cell death in CTX patients

CTX患者小脑神经细胞死亡机制

• 批准号: 09470039
• 负责人: SEYAMA Yousuke
• 金额: $ 8.38万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470039/
• 关键词: CTX; cerebellar neuronal cells; apoptosis; cholestanol; corneal endothelial cells; lens epithelial cells; 能研黄色腫症; CTX

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.

CTX是一种遗传性脂质储存疾病，其特征在于高胆固醇血症、小脑共济失调、跟腱黄瘤、白内障和过早动脉粥样硬化。小脑性共济失调和白内障的病因不明。为了阐明小脑性共济失调和白内障的病因，我们建立了含胆甾烷醇饮食的CTX大鼠模型。通过组织化学分析，胆甾烷醇沉积在透镜、角膜和小脑中。因此，我们推测胆甾烷醇可能诱导小脑神经元细胞凋亡，包括浦肯野细胞，角膜内皮细胞和透镜上皮细胞。对这些细胞进行原代培养，并将胆甾烷醇加入培养基中。通过TUNEL法、半胱氨酸蛋白酶的诱导和细胞形态学的改变来判断胆甾烷醇诱导这些细胞凋亡。本研究结果可能解释CTX患者小脑共济失调和白内障的发病机制。

项目成果

Yousuke Seyama: "Cholestanol induces apoptosis of cerebellar neuronal cells in vitro" Biochem Biophys Res Commun. (印刷中). (1999)

Yousuke Seyama：“胆固醇在体外诱导小脑神经元细胞凋亡”Biochem Biophys Res Commun（出版中）。

脊山洋右: "Cholestanol induces apoptosis of cerebellar neuronal cells in vitro" Biochem Biophys Res Commun. (印刷中). (1999)

Hirosuke Seyama：“胆固醇在体外诱导小脑神经元细胞凋亡”Biochem Biophys Res Commun（出版中）。

Chen, W., Kubota, S.Teramoto, T., Nishimura, Y., Yonemoto, K., and Seyama, Y.: "Silent nucleotide substitution in the sterol 27 hydroxylase gene (CYP27) leads to alternative pre-mRNA splicing by activating a cryptic 5' splice site at the mutant codon in c

Chen, W.、Kubota, S.Teramoto, T.、Nishimura, Y.、Yonemoto, K. 和 Seyama, Y.：“甾醇 27 羟化酶基因 (CYP27) 中的沉默核苷酸取代导致选择性前 mRNA 剪接

脊山洋右: "Genetic analysis enables definite and rapid diagnosis of cerebrotendinous xanthomatosis" NEUROLOGY. 51. 865-867 (1998)

Hirosuke Seyama：“基因分析能够明确、快速地诊断脑腱黄瘤病”NEUROLOGY 51. 865-867 (1998)。

久保田俊一郎等: "脳腱黄色腫症(CTX)における神経細胞死" The Lipid. 8(3). 277-282 (1997)

Shunichiro Kubota 等人：“脑腱黄瘤病 (CTX) 中的神经元细胞死亡”The Lipid 8(3) (1997)。