目的研究受体酪氨酸激酶样孤儿受体1(receptor tyrosine kinase like orphan receptor 1,ROR1)及微管相关蛋白1B(microtubule associated protein 1B,MAP1B)在年龄相关性白内障(age-related-cataract,ARC)患者晶状体前囊膜组织中的mRNA...目的研究受体酪氨酸激酶样孤儿受体1(receptor tyrosine kinase like orphan receptor 1,ROR1)及微管相关蛋白1B(microtubule associated protein 1B,MAP1B)在年龄相关性白内障(age-related-cataract,ARC)患者晶状体前囊膜组织中的mRNA和蛋白表达情况,并初步探讨其临床意义及蛋白表达的相关性。方法收集ARC患者晶状体前囊膜组织20例为ARC组,眼外伤发生晶状体脱出的患者15例为对照组,通过RT-qPCR、Western blot、免疫组织化学染色检测组织中ROR1与MAP1B的表达情况,利用STRING数据库预测蛋白之间相关性。结果与对照组相比,ARC组ROR1、MAP1B的mRNA表达水平[分别为(0.265±0.150)、(0.155±0.069)]呈现低表达,其蛋白表达水平[分别为(0.66±0.015)、(0.75±0.036)]呈现低表达,差异具有统计学意义(P<0.05);PPI网络显示ROR1与MAP1B蛋白呈现间接调控关系。结论ROR1与MAP1B在ARC中呈明显低表达,且二者可能以间接调控关系介导ARC的发生发展。展开更多
多系统萎缩(multiple system atrophy,MSA)是一类神经系统退行性疾病,其病理特征是胶质细胞中出现含有不溶性α突触核蛋白(α-synuclein)的胞质包涵体.研究显示,α-synuclein在多系统萎缩的发病机制中有重要作用,但其毒性的分子机制目...多系统萎缩(multiple system atrophy,MSA)是一类神经系统退行性疾病,其病理特征是胶质细胞中出现含有不溶性α突触核蛋白(α-synuclein)的胞质包涵体.研究显示,α-synuclein在多系统萎缩的发病机制中有重要作用,但其毒性的分子机制目前还不清楚.本文在前期研究氧化应激条件下α-synuclein引起细胞内钙稳态失衡,提出了以氧化应激为连接的多系统萎缩中,胶质细胞死亡的新假说的基础上,深入分析了α-synuclein过表达导致U251细胞变性死亡的分子机制.首先证明过表达α-synuclein的U251细胞出现生长速度减慢、氧化应激水平增加和钙离子瞬时受体电位通道蛋白(transient receptor potential channel-1,TRPC1)表达量升高,而且细胞存活率的变化可通过下调TRPC1的表达得以恢复,说明TRPC1在α-synuclein过表达细胞死亡中发挥了重要作用;其次,研究发现α-synuclein稳转U251细胞中出现了明显的自噬水平增加和细胞凋亡的特征,表明α-synuclein通过作用于内质网钙泵以及细胞膜上的瞬时受体电位钙通道TRPC1,破坏了细胞内的钙稳态,进而影响自噬和凋亡,增加了U251细胞对于过氧化氢的敏感性,这可能是导致多系统萎缩病人脑内胶质细胞死亡的原因.展开更多
Heat shock protein 90(Hsp90)is an abundant molecular chaperone with two isoforms,Hsp90α and Hsp90p.Hsp90β deficiency causes embryonic lethality,whereas Hsp90α deficiency causes few abnormities except male sterility...Heat shock protein 90(Hsp90)is an abundant molecular chaperone with two isoforms,Hsp90α and Hsp90p.Hsp90β deficiency causes embryonic lethality,whereas Hsp90α deficiency causes few abnormities except male sterility.In this paper,we reported that Hsp90α was exclusively expressed in the retina,testis,and brain.Its deficiency caused retinitis pigmentosa(RP),a disease leading to blindness.In Hsp90α-deficient mice,the retina was deteriorated and the outer segment of photoreceptor was deformed.Immunofluorescence staining and electron microscopic analysis revealed disintegrated Golgi and aberrant intersegmental vesicle transportation in Hsp90α-deficient photoreceptors.Proteomic analysis identified microtubule-associated protein IB(MAP1B)as an Hsp90α-associated protein in photoreceptors.Hspcx deficiency increased degradation of MAP1B by inducing its ubiquitination,causing a-tubulin deacetylation and microtubule destabilization.Furthermore,the treatment of wild-type mice with 17-DMAG,an Hsp90 inhibitor of geldanamycin derivative,induced the same retinal degeneration as Hsp90α deficiency.Taken together,the microtubule destabilization could be the underlying reason for Hsp90α deficiency-induced RP.展开更多
基金supported by the grantfrom the National Natural Science Foundation of China(31571387).
文摘Heat shock protein 90(Hsp90)is an abundant molecular chaperone with two isoforms,Hsp90α and Hsp90p.Hsp90β deficiency causes embryonic lethality,whereas Hsp90α deficiency causes few abnormities except male sterility.In this paper,we reported that Hsp90α was exclusively expressed in the retina,testis,and brain.Its deficiency caused retinitis pigmentosa(RP),a disease leading to blindness.In Hsp90α-deficient mice,the retina was deteriorated and the outer segment of photoreceptor was deformed.Immunofluorescence staining and electron microscopic analysis revealed disintegrated Golgi and aberrant intersegmental vesicle transportation in Hsp90α-deficient photoreceptors.Proteomic analysis identified microtubule-associated protein IB(MAP1B)as an Hsp90α-associated protein in photoreceptors.Hspcx deficiency increased degradation of MAP1B by inducing its ubiquitination,causing a-tubulin deacetylation and microtubule destabilization.Furthermore,the treatment of wild-type mice with 17-DMAG,an Hsp90 inhibitor of geldanamycin derivative,induced the same retinal degeneration as Hsp90α deficiency.Taken together,the microtubule destabilization could be the underlying reason for Hsp90α deficiency-induced RP.
