Hsp multichaperone complex buffers pathologically modified Tau.

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Alzheimer's disease is characterized by Tau protein misfolding and aggregation, leading to neuronal dysfunction.
• The Hsp70/Hsp90 chaperone machinery is crucial for maintaining protein homeostasis.
• The interaction between Tau and the Hsp70/Hsp90 system has not been fully understood.

Purpose of the Study:

• To investigate the interaction between Tau and the Hsp70/Hsp90 chaperone machinery.
• To elucidate the role of this interaction in Tau aggregation and protein homeostasis.
• To identify key regulators within the Hsp70/Hsp90 complex involved in Tau pathology.

Main Methods:

• Biochemical assays to study protein complex formation.
• Analysis of Tau aggregation in the presence of Hsp70/Hsp90 machinery.
• Investigation of co-chaperone and E3 ligase involvement (p23, CHIP).
• Studies using phosphorylated Tau.

Main Results:

• Tau is identified as a high-affinity substrate for the Hsp70/Hsp90 machinery.
• Complex formation between Tau and Hsp70/Hsp90 inhibits Tau aggregation.
• The co-chaperone p23 stabilizes the Tau-chaperone complex, while CHIP targets Tau for proteasomal degradation.
• Phosphorylated Tau interacts with the Hsp70/Hsp90 machinery but not Hsp90 alone.

Conclusions:

• The Hsp70/Hsp90 multichaperone complex is a critical regulator of Tau protein.
• This machinery plays a significant role in preventing Tau aggregation and promoting its degradation.
• Understanding this interaction offers potential therapeutic strategies for Alzheimer's disease and related tauopathies.