Induction Mechanism of Apoptosis in Cerebrotendinous Xanthomatosis

脑腱黄瘤病细胞凋亡的诱导机制

• 批准号: 13480201
• 负责人: SEYAMA Yousuke
• 金额: $ 8.58万
• 依托单位: Ochanomizu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13480201/
• 关键词: cerebrotendinous xanthomatosis; CTX; Purkinje cell; cholestanol; apoptosis; cerebellar symptom

Onset of CTX is usually in early teens and mental retardation is most frequently observed at this stage. Pyramidal sign and progressive cerebellar symptom appear at puberty together with atactic gait, lateral nystagmus or atactic dysphasia. Juvenile cataract also appears in late teens. Most characteristic symptom is xanthoma in brain, tendon, muscle and lung. Treatment is symptomatic therapy, and oral administration of chenodeoxycholic acid is effective to reduce the size of xan-thoma. By feeding experiments, we proved that the high concentration of cholestanol induced the accumulation of chole-stanol in cerebellum and caused the neurological disturbance. We formulated a hypothesis that cholestanol in serum of CTX patients might induce neuronal cell death in cerebellum and eventually cerebellar ataxia would occur. In the present study, we developed hypercholestanolemia rats and examined the effects of cholestanol on death of cerebellar neuronal cells, corneal endothelial and lens epith … More elial cells. Apoptosis was evident in cells cultured with cholestanol in these cells. As activities of interleukin-1β-converting enzyme (ICE) and CPP32 protease were increased in cells cultured with cholestanol, all these data taken together suggest that cholestanol induced apoptosis. Our observation may explain the mechanism of cerebellar ataxia, cataract and corneal opacities of CTX patients. We studied a 44-year old woman with progressive frontal lobe dementia and spastic araplegia. Examination revealed increased serum levels of cholestanol and heterozygous mutation of the sterol 27-hydroxylase gene (CYP27), In genomic DNA, both the G and A were found at codon 441, indicating the heterozygous pattern of the mutation of CGG441Arg to CAG441Gln. Computed tomography and magnetic resonance imaging (MRI) of the brain showed cerebral atrophy, which was marked in the frontal area. Cerebral MR images showed diffuse symmetric areas of hyperintensity in the white matter of the lateral ventricles in the optic radiation. Less

CTX通常在青少年早期发病，在这个阶段最常观察到智力迟钝。锥体征和进行性小脑症状出现于青春期，同时伴有失稳步态、侧边眼震或失稳性吞咽障碍。青少年白内障也出现在青少年晚期。最典型的症状是脑、肌腱、肌肉和肺部的黄瘤。治疗方法为对症治疗，口服鹅去氧胆酸可有效缩小瘤的大小。通过饲养实验，我们证实了高浓度的胆甾醇可引起小脑内胆甾醇的积累，引起神经功能障碍。我们提出了一个假设，CTX患者血清中的胆固醇可能导致小脑神经元细胞死亡，最终导致小脑性共济失调。本研究以高胆固醇血症大鼠为实验对象，观察胆固醇对小脑神经元细胞、角膜内皮细胞和晶状体上皮细胞死亡的影响。用胆固醇培养的细胞凋亡明显。随着白细胞介素-1β转换酶（ICE）和CPP32蛋白酶活性的升高，这些数据表明胆固醇可诱导细胞凋亡。我们的观察可能解释CTX患者小脑性共济失调、白内障和角膜混浊的发生机制。我们研究了一位患有进行性额叶痴呆和痉挛性截瘫的44岁女性。检测结果显示血清胆固醇水平升高，甾醇27-羟化酶基因（CYP27）杂合突变，基因组DNA中密码子441处同时存在G和A，表明CGG441Arg向CAG441Gln突变为杂合模式。计算机断层扫描和磁共振成像（MRI）显示大脑萎缩，在额叶区明显。脑MR图像显示视光辐射侧脑室白质弥漫性对称高强度区。少

项目成果

Sugama, S., Kimura, A., Chen, W., Kubota, S., Seyama, Y, Taira, N., Eto, Y: "Frontal lobe dementia with abnormal cholesterol metabolism and heterozygous mutation in sterol 27-hydroxylase gene (CYP 27)"J Inherit Metab Dis. 24. 379-392 (2001)

Sugama, S.、Kimura, A.、Chen, W.、Kubota, S.、Seyama, Y、Taira, N.、Eto, Y：“额叶痴呆伴胆固醇代谢异常和甾醇 27-羟化酶基因杂合突变

Tomioka M, Sameshima M, Nakano H, Kubo T, et al.: "A possible intermediate step during apoptotic execution"Hum Cell. 15. 43-51 (2002)

Tomioka M、Sameshima M、Nakano H、Kubo T 等人：“细胞凋亡执行过程中可能的中间步骤”Hum Cell。

Sugama S, Kimura A, Chen W, Kubota S, Seyama Y, et al.: "Frontal lobe dementia with abnormal cholesterol metabolism and heterozygous mutation in sterol 27-hydroxylas gene (CYP 27)"J Inherit Metab Dis. 24. 379-392 (2001)

Sugama S、Kimura A、Chen W、Kubota S、Seyama Y 等人：“伴有胆固醇代谢异常和甾醇 27-羟化酶基因 (CYP 27) 杂合突变的额叶痴呆”J Inherit Metab Dis。

Cui Y, Otsuka M, Fujiwara, Y.: "Reduction of dehydroerythorbic acid in vitamin C-deficient guinea pigs"J. Nutr. Sci, Vitaminol. 47. 316-320 (2001)

Cui Y，Otsuka M，Fujiwara，Y.：“维生素 C 缺乏豚鼠中脱氢异抗坏血酸的减少”J。

Sugama S, Kimura A, Chen W, Kubota S, Seyama Y, Taira N, Eto Y.: "Frontal lobe dementia with abnormal cholesterol metabolism and heterozygous mutation in sterol 27-hydroxylase gene (CYP27)"Journal of Inherited Metabolic Disease. 24(3). 379-392 (2001)

Sugama S、Kimura A、Chen W、Kubota S、Seyama Y、Taira N、Eto Y.：“胆固醇代谢异常和甾醇 27-羟化酶基因 (CYP27) 杂合突变的额叶痴呆”遗传代谢疾病杂志。