Mutations in tau reduce its microtubule binding properties in intact cells and affect its phosphorylation

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Tau protein is crucial for microtubule stability.
• Mutations in tau are linked to frontotemporal dementia (FTD).
• Altered tau function may contribute to FTD pathogenesis.

Purpose of the Study:

• To quantify the impact of tau isoform differences and mutations on tau's physiological function in a cellular context.
• To investigate how specific tau mutations affect microtubule assembly and extension.

Main Methods:

• Utilized a cellular assay to measure tau's effect on microtubule extension.
• Transfected cells with different tau variants, including wild-type and mutated forms.
• Quantified microtubule extension and tau phosphorylation levels.

Main Results:

• All tau variants bound to microtubules, but microtubule extension was reduced with 3-repeat tau compared to 4-repeat tau.
• Mutations P301L and V337M significantly reduced microtubule extension, with P301L having a more pronounced effect.
• The R406W mutation showed a minimal effect on microtubule extension but resulted in less tau phosphorylation in cells.

Conclusions:

• Tau isoform differences and specific mutations impact tau's ability to promote microtubule extension.
• These findings highlight the role of altered tau function in frontotemporal dementia.
• The R406W mutation's effect on phosphorylation warrants further investigation.