The p38 pathway is activated in Pick disease and progressive supranuclear palsy: a mechanistic link between mitogenic pathways, oxidative stress, and tau.
In Pick disease and progressive supranuclear palsy (PSP), accumulations of phosphorylated tau are associated with oxidative stress, although the mechanism linking these features remains unknown. However, we suspected that the oxidative stress-induced activation of mitogen-activated protein kinases might lead to tau phosphorylation and accumulation as characteristic inclusion bodies. To test this notion, we investigated whether the activation of mitogen-activated protein kinases is involved in the pathogenesis of Pick disease and PSP. Our results show that the lesions of both Pick disease and PSP are associated with the activation of the p38 pathway (phospho-MKK6 and phospho-p38), one of the best characterized of the mitogen-activated protein kinase pathways. Based on these findings, we propose that the phosphorylation of tau is a direct consequence of the oxidative stress-induced activation of mitogen-activated protein kinases, including p38.
Hartzler
Anthony W
AW
Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA.
Zhu
Xiongwei
X
Siedlak
Sandra L
SL
Castellani
Rudolph J
RJ
Avilá
Jesus
J
Perry
George
G
Smith
Mark A
MA
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D048669:MAP Kinase Kinase 6; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D020774:Pick Disease of the Brain / Q000378:metabolism* / Q000473:pathology; D013494:Supranuclear Palsy, Progressive / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human