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The environmental toxin arsenite induces tau hyperphosphorylation.
Benoit I Giasson1, Deepak M Sampathu, Christina A Wilson
1University of Pennsylvania School of Medicine, Third Floor Maloney Building, 3600 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Biochemistry
|December 18, 2002
Summary
Environmental toxin arsenite significantly increases tau hyperphosphorylation, a hallmark of Alzheimer's disease. This study identifies specific tau phosphorylation sites affected by arsenite and explores its impact on tau mutations, suggesting environmental factors contribute to neurodegeneration.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- Paired helical filaments from hyperphosphorylated tau are key in Alzheimer's disease neuron demise.
- Understanding tau phosphorylation's regulation is crucial for neurodegenerative disease research.
Purpose of the Study:
- To investigate the effect of the environmental toxin arsenite on tau phosphorylation.
- To identify specific tau phosphorylation sites altered by arsenite exposure.
- To examine the influence of arsenite on tau mutations linked to frontotemporal dementia.
Main Methods:
- Treatment of tau with arsenite.
- Phosphopeptide mapping to quantify phosphorylation.
- Analysis of tau mutations (DeltaKappa280, V337M, R406W) phosphorylation.
- Inhibition studies using roscovitine.
Main Results:
- Arsenite significantly increased phosphorylation at multiple tau residues (Thr-181, Ser-202, Thr-205, Thr-231, Ser-262, Ser-356, Ser-396, Ser-404).
- Arsenite-induced tau phosphorylation was not mediated by ERK1/2, SAPK, GSK-3, or PP1/2.
- Roscovitine inhibited the arsenite-induced tau hyperphosphorylation.
- Arsenite altered phosphorylation patterns in tau mutations, particularly R406W.
Conclusions:
- Environmental toxins like arsenite can induce tau hyperphosphorylation, potentially contributing to neurodegeneration.
- Specific tau mutations affect phosphorylation patterns in response to arsenite.
- The precise kinase responsible for arsenite-induced tau hyperphosphorylation remains unidentified.