The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Alzheimer's disease (AD) is characterized by neurofibrillary tangles of hyperphosphorylated tau (p-tau).
• Targeting p-tau clearance is a potential therapeutic avenue for AD and other tauopathies.

Purpose of the Study:

• To investigate the role of Heat Shock Protein 90 (Hsp90) in the regulation of p-tau.
• To explore Hsp90 inhibition as a therapeutic strategy for reducing p-tau accumulation.

Main Methods:

• Inhibition of Hsp90 in cellular and animal models.
• Assessment of p-tau levels and degradation pathways.
• Evaluation of Hsp90 inhibitor efficacy in a mouse model of tauopathy.

Main Results:

• Hsp90 inhibition decreased p-tau levels independently of heat shock factor 1 (HSF1) activation.
• Carboxy terminus of Hsp70-interacting protein (CHIP), a tau ubiquitin ligase, mediated Hsp90-dependent p-tau reduction.
• Blockade of the Hsp90 refolding pathway enhanced p-tau turnover via degradation.
• Peripheral administration of an Hsp90 inhibitor reduced p-tau in a tauopathy mouse model.

Conclusions:

• Hsp90 plays a critical role in the pathogenesis of tauopathies.
• Hsp90 inhibition promotes p-tau degradation and represents a promising therapeutic strategy for AD and related disorders.
• Targeting Hsp90 offers a novel approach for developing treatments for neurodegenerative diseases characterized by tau pathology.