title: Parkinson's disease-associated DJ-1 mutations increase abnormal phosphorylation of tau protein through Akt/GSK-3β pathways.
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.
authors: Department of Neurosurgery, Xijing Hospital of the Fourth Military Medical University, No. 127 West Changle Road, Xi'an, 710032, Shaanxi Province, People's Republic of China.
authors: Yangang
authors: Y
authors: Wang
authors: Weiping
authors: W
authors: Liu
authors: Xiaosheng
authors: X
authors: He
authors: Fei
authors: F
authors: Zhou
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D018021:Lithium Chloride / Q000494:pharmacology; D051379:Mice; D020125:Mutation, Missense; D015513:Oncogene Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics; D054464:Peroxiredoxins; D010766:Phosphorylation; D000071617:Protein Deglycase DJ-1; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D015513:Oncogene Proteins; D016875:tau Proteins; D054464:Peroxiredoxins; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D018021:Lithium Chloride
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