Abstract
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-1L166P and DJ-1D149A, 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)-3β phosphorylation at serine 9 (Ser9) decreases around 50 % in DJ-1L166P- or DJ-1D149A-transfected cells, while there is no change in total levels of GSK-3β. Our results also indicate that overexpression of DJ-1L166P or DJ-1D149A leads to a significant decrease in the level of phosphorylation of Akt at Thr308, which plays a critical role in phosphorylating GSK-3β at Ser9 and inhibiting its kinase activity. Importantly, insulin, the activator for Akt, effectively attenuates the reduced phosphorylation level of GSK-3β at Ser9 induced by DJ-1L166P. 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-1L166P and DJ-1D149A mutations increase tau phosphorylation by increasing the activity of GSK-3β. Finally, we found that administration of lithium chloride, a well-known GSK-3β inhibitor, resulted in decreased levels of phosphorylated tau in DJ-1L166P-transfected cells.
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Wang, Y., Liu, W., He, X. et al. Parkinson's Disease-Associated Dj-1 Mutations Increase Abnormal Phosphorylation of Tau Protein through Akt/Gsk-3β Pathways. J Mol Neurosci 51, 911–918 (2013). https://doi.org/10.1007/s12031-013-0099-0
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DOI: https://doi.org/10.1007/s12031-013-0099-0