Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Alzheimer's disease (AD) is characterized by progressive memory loss and cognitive impairment.
• Postsynaptic localization of microtubule-associated protein Tau (Tau) is linked to cognitive deficits in AD.
• The precise role of Tau in postsynaptic dysfunction remains incompletely understood.

Purpose of the Study:

• To elucidate the molecular mechanism by which Tau influences postsynaptic protein dynamics.
• To investigate the interaction between Tau and key postsynaptic density (PSD) proteins.
• To explore potential therapeutic targets for modulating Tau-mediated synaptic dysfunction.

Main Methods:

• In vitro studies using purified proteins to assess Tau's effect on liquid-like protein droplets.
• Biophysical techniques to analyze Tau binding to PSD-95.
• Experiments with synthetic membranes to model NMDA receptor clusters.
• Investigating the impact of competitive peptide binding on protein dynamics.

Main Results:

• Tau was shown to arrest liquid-like droplets of PSD-95, GKAP, Shank, and Homer proteins.
• Tau binding to the GMP-binding pocket of PSD-95 was identified as crucial for this arrest.
• Tau-mediated arrest of NMDA-receptor-associated protein clusters on synthetic membranes was observed.
• Competitive binding of a phosphorylated peptide to PSD-95 rescued the dynamics of NMDA receptor constructs.

Conclusions:

• Tau modulates the dynamic properties of the postsynaptic density by arresting protein clusters.
• This Tau-mediated arrest mechanism offers a new perspective on synaptic dysfunction in Alzheimer's disease.
• Targeting the Tau-PSD-95 interaction may represent a therapeutic strategy for AD.