Protease-resistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion
Protease-resistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion
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DOI：
10.1111/j.1440-1789.2011.01245.x
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发表时间：
2012-04-01
期刊：
影响因子：
2.3
通讯作者：
Iwaki, Toru
中科院分区：
文献类型：
--
作者：
Honda, Hiroyuki;Sasaki, Kensuke;Iwaki, Toru
脑室内输注戊聚糖多硫酸酯（PPS）治疗各种人类朊病毒疾病已在日本得到应用。为了评价PPS治疗的影响，我们对PPS治疗的尸检脑组织（1例散发性克雅氏病（sCJD，病例1），2例硬脑膜移植物相关性克雅氏病（dCJD，病例2和4），1例Gerstmann-Straussler-Scheinker病（GSS，病例3））中的PrP分子进行了病理学检查和生化分析。6例未接受PPS治疗的sCJD患者进行了对比研究。蛋白酶K消化后，通过Western印迹法评价额叶中的蛋白酶抗性PrP（PrPres）。此外，PrP分子的聚合度通过尺寸排阻凝胶色谱法测定来检查。PPS输注在疾病发作后310个月开始，但治疗未实现任何临床改善。经治疗病例的尸检显示对称性脑损伤，包括神经元丢失、海绵状变化和神经胶质增生。值得注意的是，尽管有星形胶质细胞增生，但所有治疗病例中皮质星形胶质细胞中的GFAP均减少。PrP免疫组化显示异常突触沉积在所有治疗的情况下，进一步斑块型PrP沉积的情况下3 GSS和情况下4 dCJD。Western blotting显示dCJD病例2和GSS病例3中PrPres的比例相对较低，而在治疗的sCJD（病例1）中，PrPres的比例与未治疗的病例相当。1例sCJD（病例1）和1例dCJD（病例2）的PrP寡聚体指数降低。虽然脑室内输注PPS可能会改变朊病毒病患者脑内PrP寡聚体的积聚，但其治疗效果仍不确定。
Intraventricular infusion of pentosan polysulfate (PPS) as a treatment for various human prion diseases has been applied in Japan. To evaluate the influence of PPS treatment we performed pathological examination and biochemical analyses of PrP molecules in autopsied brains treated with PPS (one case of sporadic Creutzfeldt-Jakob disease (sCJD, case 1), two cases of dura mater graft-associated CJD (dCJD, cases 2 and 4), and one case of Gerstmann-Straussler-Scheinker disease (GSS, case 3). Six cases of sCJD without PPS treatment were examined for comparison. Protease-resistant PrP (PrPres) in the frontal lobe was evaluated by Western blotting after proteinase K digestion. Further, the degree of polymerization of PrP molecules was examined by the size-exclusion gel chromatography assay. PPS infusions were started 310 months after disease onset, but the treatment did not achieve any clinical improvements. Postmortem examinations of the treated cases revealed symmetrical brain lesions, including neuronal loss, spongiform change and gliosis. Noteworthy was GFAP in the cortical astrocytes reduced in all treated cases despite astrogliosis. Immunohistochemistry for PrP revealed abnormal synaptic deposits in all treated cases and further plaque-type PrP deposition in case 3 of GSS and case 4 of dCJD. Western blotting showed relatively low ratios of PrPres in case 2 of dCJD and case 3 of GSS, while in the treated sCJD (case 1), the ratio of PrPres was comparable with untreated cases. The indices of oligomeric PrP were reduced in one sCJD (case 1) and one dCJD (case 2). Although intraventricular PPS infusion might modify the accumulation of PrP oligomers in the brains of patients with prion diseases, the therapeutic effects are still uncertain.