DnaJC7 specifically regulates tau seeding.

Area of Science:

• Neurobiology
• Molecular Biology
• Protein Biochemistry

Background:

• Neurodegenerative tauopathies result from toxic tau protein accumulation.
• Chaperone proteins, including Hsp70s and J domain proteins (JDPs), regulate protein folding, but their specific roles in tauopathies are unclear.
• The JDP DnaJC7 is known to bind tau and inhibit its aggregation.

Approach:

• Utilized proteomics in a cell model to identify proteins interacting with insoluble tau.
• Performed individual knockouts of JDPs to assess their impact on intracellular tau aggregation and seeding.
• Investigated the role of DnaJC7's J domain (JD) in Hsp70 binding and its effect on tau aggregation.

Key Points:

• DnaJC7 co-purified with insoluble tau and colocalized with intracellular tau aggregates.
• DnaJC7 knockout increased intracellular tau seeding and impaired aggregate clearance.
• DnaJC7's protective function against tau aggregation depends on its J domain binding to Hsp70.
• Disease-associated mutations in DnaJC7 abrogated its protective activity.

Conclusions:

• DnaJC7 specifically regulates tau aggregation through cooperation with Hsp70.
• DnaJC7 plays a critical role in preventing the seeding and accumulation of toxic tau species.
• Understanding DnaJC7-Hsp70 interactions may offer therapeutic strategies for neurodegenerative tauopathies.