期刊
JOURNAL OF MOLECULAR NEUROSCIENCE
卷 51, 期 3, 页码 911-918出版社
HUMANA PRESS INC
DOI: 10.1007/s12031-013-0099-0
关键词
Parkinson's disease; DJ-1 familial mutations; Tau phosphorylation; GSK-3 beta; Akt
Hyperphosphorylated tau protein is the main component of neurofibrillary tangles found in Alzheimer's disease and Parkinson's disease (PD). Mutations in DJ-1 have been identified as the causative gene for Parkinson's disease 7 (PARK7)-linked PD. DJ-1(L166P) and DJ-1(D149A), two types of DJ-1 mutations, are most commonly studied as the loss-of-function mutations responsible for early-onset familial PD. Whether mutations in DJ-1 result in tauopathy is as yet unknown. In this study, we found that the L166P and D149A mutant isoforms of DJ-1 associated with familial PD cause tau phosphorylation at Ser202, Ser262, and PHF1 (396/404) sites in neuroblastoma 2a cells. Glycogen synthase kinase (GSK)-3 beta phosphorylation at serine 9 (Ser9) decreases around 50 % in DJ-1(L166P)- or DJ-1(D149A)-transfected cells, while there is no change in total levels of GSK-3 beta. Our results also indicate that overexpression of DJ-1(L166P) or DJ-1(D149A) leads to a significant decrease in the level of phosphorylation of Akt at Thr308, which plays a critical role in phosphorylating GSK-3 beta at Ser9 and inhibiting its kinase activity. Importantly, insulin, the activator for Akt, effectively attenuates the reduced phosphorylation level of GSK-3 beta at Ser9 induced by DJ-1(L166P). Neither the expression of cyclin-dependent kinase 5 nor the level of PP2A activity was found to have changed, suggesting that the familial PD-associated DJ-1(L166P) and DJ-1(D149A) mutations increase tau phosphorylation by increasing the activity of GSK-3 beta. Finally, we found that administration of lithium chloride, a well-known GSK-3 beta inhibitor, resulted in decreased levels of phosphorylated tau in DJ-1(L166P)-transfected cells.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据