Parkinson's Disease-Associated Dj-1 Mutations Increase Abnormal Phosphorylation of Tau Protein through Akt/Gsk-3β Pathways

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.