Peripheral proteasome and caspase activity in Parkinson disease and Alzheimer disease
Peripheral proteasome and caspase activity in Parkinson disease and Alzheimer disease
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DOI：
10.1212/01.wnl.0000198511.09968.b3
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发表时间：
2006-02-28
期刊：
影响因子：
9.9
通讯作者：
Martignoni, E
中科院分区：
文献类型：
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作者：
Blandini, F;Sinforiani, E;Martignoni, E
背景资料：泛素-蛋白酶体（UP）系统是降解多泛素化蛋白的多催化复合物，其缺陷可通过诱导促凋亡条件干预以蛋白质聚集体的细胞内形成为特征的神经退行性疾病（如帕金森病（PD）和阿尔茨海默病（AD））的发病机制。研究方法：作者测量了PD和AD患者外周血淋巴细胞（PBL）中蛋白水解UP核心、蛋白酶体20 S和促凋亡caspase-3和-9的活性，以确定这些系统的变化是否可在外周检测到。结果如下：与健康对照相比，治疗的PD患者的PBL中蛋白酶体20 S活性降低（平均值+/- SEM：1.0 +/- 0.1 vs 2.3 +/- 0.2 nmol 7-氨基-4-甲基香豆素（AMC）/10（6）个细胞，p < 0.001），而caspase-3活性的显著增加（1370 +/- 153 vs 586 +/- 104 pmol AMC/10（6）细胞，p < 0.001）和半胱天冬酶-9活性在未经治疗的PD患者的PBL中也检测到增加的半胱天冬酶-9活性（900 +/-193 U/10（6）细胞）。PD持续时间和严重程度（统一帕金森病评定量表评分）与蛋白酶体20 S活性呈负相关，与caspase-3活性呈直接相关。在PD患者中还观察到caspase-3活性与蛋白酶体20 S活性之间呈负相关。AD患者蛋白酶体20 S或半胱天冬酶活性或生化和临床变量之间的相关性无显着变化。结论：帕金森病患者外周血淋巴细胞中可检测到蛋白酶体活性的降低（可能与半胱天冬酶活化有关），但阿尔茨海默病患者中未检测到，这表明这些变量可能被考虑用于帕金森病外周生物标志物的开发。
Background: Defects of the ubiquitin-proteasome (UP) system, a multicatalytic complex degrading polyubiquitinated proteins, may intervene in the pathogenesis of neurodegenerative disorders characterized by intracellular formation of protein aggregates such as Parkinson disease (PD) and Alzheimer disease (AD) by inducing proapoptotic conditions. Methods: The authors measured the activity of proteolytic UP core, proteasome 20S, and of proapoptotic caspase-3 and -9 in peripheral blood lymphocytes (PBLs) of PD and AD patients to establish whether changes in these systems are detectable peripherally. Results: Proteasome 20S activity was reduced in PBLs of treated PD patients vs healthy controls (mean +/- SEM: 1.0 +/- 0.1 vs 2.3 +/- 0.2 nmol 7-amino-4-methylcoumarin (AMC)/10(6) cells, p < 0.001), whereas marked increases in caspase-3 activity (1370 +/- 153 vs 586 +/- 104 pmol AMC/10(6) cells, p < 0.001) and caspase-9 activity (873 +/- 86 vs 304 +/- 27 U/10(6) cells, p < 0.001) were found. Increased caspase-9 activity was also detected in PBLs of untreated PD patients (900 +/- 193 U/10(6) cells). PD duration and severity (Unified Parkinson's Disease Rating Scale score) were inversely correlated with proteasome 20S activity and directly correlated with caspase-3 activity. An inverse correlation was also observed in PD patients between caspase-3 activity and proteasome 20S activity. No significant changes in proteasome 20S or caspase activity or correlations between biochemical and clinical variables were found in patients with AD. Conclusions: A decrease in proteasome activity, possibly related to caspase activation, is detectable in peripheral blood lymphocytes of patients with Parkinson disease but not patients with Alzheimer disease, suggesting that these variables may be considered for the development of peripheral biomarkers of Parkinson disease.