Disruption of tubulin-alpha4a polyglutamylation prevents aggregation of hyper-phosphorylated tau and microglia...

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Tauopathies are characterized by hyper-phosphorylated Tau dissociation from microtubules and aggregate formation.
• Tubulin polyglutamylation, a posttranslational modification, alters the Tau-microtubule interaction.
• The role of tubulin polyglutamylation in Tau pathology in vivo remains unclear.

Purpose of the Study:

• To investigate the in vivo contribution of tubulin polyglutamylation to Tau pathology.
• To determine if substrate-specific abolition of Tuba4a polyglutamylation impacts Tau phosphorylation and aggregation.

Main Methods:

• Generated a knock-in mouse model with mutations abolishing Tuba4a polyglutamylation in a substrate-specific manner.
• Crossbred Tuba4a knock-in mice with the hTau tauopathy mouse model.
• Assessed Tau phosphorylation, aggregation, and microglia activation.

Main Results:

• Abolishing Tuba4a polyglutamylation prevented Tau and GSK3 kinase binding to neuronal microtubules.
• Reduced phospho-Tau levels were observed in Tuba4a knock-in mice.
• Crossbreeding reversed Tau hyper-phosphorylation and oligomerization, normalizing microglia activation in the hTau model.

Conclusions:

• Tubulin polyglutamylation is a key factor in Tau pathology development.
• Targeting tubulin polyglutamylation may represent a novel therapeutic strategy for tauopathies.
• This study provides in vivo evidence for the role of tubulin polyglutamylation in neurodegenerative disease.