NUB1 modulation of GSK3β reduces tau aggregation

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Abnormal tau phosphorylation is linked to neurodegenerative diseases like Alzheimer's.
• Glycogen synthase kinase 3β (GSK3β) is implicated in pathological tau hyperphosphorylation.
• The role of Nedd8 ultimate buster 1 (NUB1) in tau pathology is unclear.

Purpose of the Study:

• To investigate the function of NUB1 in neuropathogenic tau phosphorylation and aggregation.
• To elucidate the mechanism by which NUB1 affects tau pathology and GSK3β.

Main Methods:

• Co-immunoprecipitation assays to study protein interactions.
• Cellular models to assess tau phosphorylation and aggregation.
• NUB1 domain deletion mutants to identify functional regions.
• NUB1 gene silencing to observe endogenous protein effects.

Main Results:

• NUB1 interacts with tau and GSK3β, disrupting their association and GSK3β recruitment to tau inclusions.
• NUB1 reduces GSK3β-mediated tau phosphorylation and aggregation.
• NUB1 induces GSK3β degradation, with the UBL domain essential for degradation and the UBA domain critical for GSK3β interaction and tau aggregation suppression.
• NUB1 silencing leads to GSK3β stabilization and increased tau phosphorylation.

Conclusions:

• NUB1 plays a critical role in neurodegeneration by modulating tau phosphorylation and aggregation through regulation of GSK3β levels.
• NUB1's interaction with GSK3β and its domains are crucial for its function in tau pathology.
• NUB1 represents a potential therapeutic target for tauopathies.