Promoting Secretion of Pathological Tau Species Using an Induced Proximity Platform That Engages the Autophagy...

Area of Science:

• Neuroscience
• Cell Biology
• Drug Discovery

Background:

• Aberrantly phosphorylated aggregated tau protein accumulation causes neuronal dysfunction in neurodegenerative diseases.
• Targeted protein degradation (TPD) using the autophagy-lysosome pathway (ALP) is a therapeutic strategy to reduce protein aggregates.
• Developing methods to clear toxic tau species is crucial for treating these diseases.

Purpose of the Study:

• To develop a novel heterobifunctional molecule (MRL828) for targeted degradation of aggregated tau proteins.
• To investigate the mechanism of action for MRL828 in clearing intracellular tau aggregates.
• To explore the potential of MRL828 as a therapeutic strategy for neurodegenerative diseases.

Main Methods:

• Design and synthesis of a heterobifunctional molecule (MRL828) combining a tau-binding ligand and an autophagy-targeting moiety.
• Treatment of cells with MRL828 to assess its effect on intracellular tau aggregates.
• Investigation of the role of autophagosomes and lysosomes in MRL828-mediated tau clearance using specific inhibitors and markers.
• Analysis of tau species secretion following MRL828 treatment.

Main Results:

• MRL828 selectively targets aggregated tau proteins.
• MRL828-induced reduction of intracellular tau aggregates is dependent on autophagosomes but not lysosomes.
• MRL828 promotes the autophagosome-dependent secretion of oligomeric and phosphorylated tau species.
• This suggests a novel mechanism of tau clearance via secretory autophagy.

Conclusions:

• MRL828 represents a novel autophagy-targeting chimera molecule.
• The primary mechanism of action involves autophagosome-dependent secretion of tau, not lysosomal degradation.
• This study reveals a new strategy for cellular removal of aggregated proteins, particularly tau, via secretory autophagy.