The environmental toxin arsenite induces tau hyperphosphorylation.
Abnormally hyperphosphorylated tau polymers known as paired helical filaments constitute one of the major characteristic lesions that lead to the demise of neurons in Alzheimer's disease. Here, we demonstrate that the environmental toxin arsenite causes a significant increase in the phosphorylation of several amino acid residues (Thr-181, Ser-202, Thr-205, Thr-231, Ser-262, Ser-356, Ser-396, and Ser-404) in tau, which are also hyperphosphorylated under pathological conditions. Complementary phosphopeptide mapping revealed a dramatic increase in the (32)P-labeling of many peptides in tau following arsenite treatment. Although arsenite activates extracellular-signal regulated kinases-1/-2 and stress-activated protein kinases, these enzymes did not contribute to the arsenite-increased phosphorylation, nor did they appear to normally modify tau in vivo. Tau phosphorylation induced by arsenite did not involve glycogen synthase kinase-3 or protein phosphatase-1 or -2, but the activity responsible for tau hyperphosphorylation could be inhibited with the protein kinase inhibitor roscovitine. The effects of arsenite on the phosphorylation of some tau mutations (DeltaKappa280, V337M, and R406W) associated with frontal-temporal dementia with parkinsonism linked to chromosome 17 was analyzed. The unchallenged and arsenite-induced phosphorylation of some mutant proteins, especially R406W, was altered at several phosphorylation sites, indicating that these mutations can significantly affect the structure of tau in vivo. Although the major kinase(s) involved in aberrant tau phosphorylation remains elusive, these results indicate that environmental factors, such as arsenite, may be involved in the cascade leading to deregulation of tau function associated with neurodegeneration.
Giasson
Benoit I
BI
University of Pennsylvania School of Medicine, Third Floor Maloney Building, 3600 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Sampathu
Deepak M
DM
Wilson
Christina A
CA
Vogelsberg-Ragaglia
Vanessa
V
Mushynski
Walter E
WE
Lee
Virginia M-Y
VM
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D016466:CHO Cells / Q000378:metabolism / Q000821:virology; D002460:Cell Line / Q000378:metabolism / Q000821:virology; D006224:Cricetinae; D004785:Environmental Pollutants / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012672:Semliki forest virus / Q000235:genetics; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D018053:Arsenites; D004785:Environmental Pollutants; D010750:Phosphoproteins; D016875:tau Proteins; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; C015001:arsenite