Sites of phosphorylation in tau and factors affecting their regulation

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Tau protein is a key component of paired helical filaments (PHFs) in Alzheimer's disease.
• PHF-tau exhibits extensive phosphorylation at numerous sites, many being proline-directed.
• Identifying kinases responsible for tau phosphorylation is crucial for understanding Alzheimer's pathogenesis.

Purpose of the Study:

• To investigate the role of proline-directed kinases in tau phosphorylation.
• To compare the phosphorylation efficiency of various kinases on tau.
• To examine the impact of tau mutations on phosphorylation by specific kinases.

Main Methods:

• In vitro kinase assays using purified tau and identified kinases.
• Phosphorylation studies in transfected cells and primary neurons.
• Site-directed mutagenesis to create tau variants, including the R406W mutation.

Main Results:

• Glycogen synthase kinase-3 (GSK-3) was identified as a major kinase phosphorylating tau at multiple proline-directed sites.
• Extracellular signal-related kinase-1/2, p38 kinase, and c-jun N-terminal kinase also phosphorylated tau, but with varying efficiencies.
• GSK-3 demonstrated more extensive tau phosphorylation in cellular models compared to other proline-directed kinases.
• The Arg406-->Trp (R406W) tau mutation altered tau phosphorylation in vitro and in cellular assays.

Conclusions:

• GSK-3 plays a significant role in the hyperphosphorylation of tau, a hallmark of Alzheimer's disease.
• Specific tau mutations can modulate kinase activity and phosphorylation patterns.
• Understanding kinase-substrate interactions in tau phosphorylation is vital for developing therapeutic strategies for Alzheimer's disease.