Parkin promotes intracellular Aβ1-42 clearance
Parkin promotes intracellular Aβ1-42 clearance
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DOI：
10.1093/hmg/ddp258
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发表时间：
2009-09-01
影响因子：
3.5
通讯作者：
Moussa, Charbel E. -H.
中科院分区：
文献类型：
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作者：
Burns, Mark P.;Zhang, Lihua;Moussa, Charbel E. -H.
阿尔茨海默病和帕金森病是常见的神经退行性疾病，可能具有一些共同的发病机制。在阿尔茨海默病和路易体痴呆中，β（1 - 42）片段在细胞内以及细胞外以淀粉样斑块的形式被发现。帕金是一种E3 - 泛素连接酶，参与细胞内蛋白质的蛋白酶体降解。帕金基因突变会导致其功能丧失，进而引发早发性帕金森综合征。在此我们测试了帕金的泛素连接酶活性是否会导致细胞内人β（1 - 42）减少。我们使用编码人帕金或人β（1 - 42）的慢病毒构建体来感染M17神经母细胞瘤细胞。帕金的表达导致细胞内人β（1 - 42）水平降低，并保护M17细胞免受其毒性影响。将慢病毒构建体共同注射到对照大鼠初级运动皮层表明，帕金的共表达在体内降低了人β（1 - 42）水平以及β（1 - 42）诱导的神经元变性。帕金提高了蛋白酶体活性，而蛋白酶体抑制阻断了帕金降低β（1 - 42）水平的作用。在帕金存在的情况下，将β（1 - 42）细胞裂解物与泛素一起孵育，证明了β - 泛素复合物的产生。这些数据表明，帕金促进细胞内β（1 - 42）的泛素化和蛋白酶体降解，并在有β沉积的神经退行性疾病中显示出保护作用。
Alzheimer's disease and Parkinson's disease are common neurodegenerative diseases that may share some underlying mechanisms of pathogenesis. A beta(1-42) fragments are found intracellularly, and extracellularly as amyloid plaques, in Alzheimer's disease and in dementia with Lewy Bodies. Parkin is an E3-ubiquitin ligase involved in proteasomal degradation of intracellular proteins. Mutations in parkin, which result in loss of parkin function, lead to early onset Parkinsonism. Here we tested whether the ubiquitin ligase activity of parkin could lead to reduction in intracellular human A beta(1-42). Lentiviral constructs encoding either human parkin or human A beta(1-42) were used to infect M17 neuroblastoma cells. Parkin expression resulted in reduction of intracellular human A beta(1-42) levels and protected against its toxicity in M17 cells. Co-injection of lentiviral constructs into control rat primary motor cortex demonstrated that parkin co-expression reduced human A beta(1-42) levels and A beta(1-42)-induced neuronal degeneration in vivo. Parkin increased proteasomal activity, and proteasomal inhibition blocked the effects of parkin on reducing A beta(1-42) levels. Incubation of A beta(1-42) cell lysates with ubiquitin, in the presence of parkin, demonstrated the generation of A beta-ubiquitin complexes. These data indicate that parkin promotes ubiquitination and proteasomal degradation of intracellular A beta(1-42) and demonstrate a protective effect in neurodegenerative diseases with A beta deposits.