Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains.
Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains.
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DOI：
10.1002/ana.23614
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发表时间：
2012-09
影响因子：
11.2
通讯作者：
Schapira, Anthony H. V.
中科院分区：
文献类型：
--
作者：
Gegg, Matthew E.;Burke, Derek;Heales, Simon J. R.;Cooper, J. Mark;Hardy, John;Wood, Nicholas W.;Schapira, Anthony H. V.
葡萄糖脑苷脂酶基因（GBA）突变是帕金森病（PD）的重要危险因素。我们研究了携带杂合子GBA突变（PD+GBA）的PD脑和散发性PD脑中葡萄糖脑苷脂酶（GCase）的酶活性。在PD+GBA（n = 9-14）和散发性PD脑（n = 12-14）的小脑、额叶皮质、壳核、杏仁核和黑质中使用荧光测定法测量GCase活性。通过蛋白质印迹法测定GCase和其他溶酶体蛋白的蛋白质表达。在体外研究了GCase、α-synuclein与线粒体功能的关系。在除额叶皮质外的所有PD+GBA脑区中观察到GCase活性显著降低。最大的缺陷是在黑质（减少58%; p < 0.01）。在散发性PD脑的黑质（减少33%; p < 0.05）和小脑（减少24%; p < 0.05）中，GCase活性也显著降低。PD+GBA和PD脑中GCase蛋白表达较低，而C/EBP同源蛋白和结合免疫球蛋白蛋白水平增加表明未折叠蛋白反应被激活。培养细胞中α-突触核蛋白水平升高或PTEN诱导的推定激酶1缺陷对GCase蛋白水平有显著影响。具有GBA突变的PD脑中的GCase缺陷是催化活性降低和蛋白水平降低的组合。这在黑质中最为明显。PD发病机制中涉及的生化变化影响体外野生型GCase蛋白表达，这些可能是在散发性PD脑中观察到的GCase缺乏的促成因素。神经网络2012;72：455-463。
Mutations in the glucocerebrosidase gene (GBA) represent a significant risk factor for developing Parkinson disease (PD). We investigated the enzymatic activity of glucocerebrosidase (GCase) in PD brains carrying heterozygote GBA mutations (PD+GBA) and sporadic PD brains. GCase activity was measured using a fluorescent assay in cerebellum, frontal cortex, putamen, amygdala, and substantia nigra of PD+GBA (n = 9–14) and sporadic PD brains (n = 12–14). Protein expression of GCase and other lysosomal proteins was determined by western blotting. The relation between GCase, α-synuclein, and mitochondria function was also investigated in vitro. A significant decrease in GCase activity was observed in all PD+GBA brain areas except the frontal cortex. The greatest deficiency was in the substantia nigra (58% decrease; p < 0.01). GCase activity was also significantly decreased in the substantia nigra (33% decrease; p < 0.05) and cerebellum (24% decrease; p < 0.05) of sporadic PD brains. GCase protein expression was lower in PD+GBA and PD brains, whereas increased C/EBP homologous protein and binding immunoglobulin protein levels indicated that the unfolded protein response was activated. Elevated α-synuclein levels or PTEN-induced putative kinase 1 deficiency in cultured cells had a significant effect on GCase protein levels. GCase deficiency in PD brains with GBA mutations is a combination of decreased catalytic activity and reduced protein levels. This is most pronounced in the substantia nigra. Biochemical changes involved in PD pathogenesis affect wild-type GCase protein expression in vitro, and these could be contributing factors to the GCase deficiency observed in sporadic PD brains. ANN NEUROL 2012;72:455–463.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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作者：
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通讯作者：
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