Data from: DnaJC7 specifically regulates tau seeding

Neurodegenerative tauopathies are caused by the accumulation of toxic tau
protein assemblies. This appears to involve template-based seeding events,
whereby tau monomer changes conformation and is recruited to a growing
aggregate. Several large families of chaperone proteins, including Hsp70s
and J domain proteins (JDPs), cooperate to regulate the folding of
intracellular proteins such as tau, but the factors that coordinate this
activity are not well known. The JDP DnaJC7 binds tau and reduces its
intracellular aggregation. However, it is unknown whether this is specific
to DnaJC7 or if other JDPs might be similarly involved. We used proteomics
within a cell model to determine that DnaJC7 co-purified with insoluble
tau and colocalized with intracellular aggregates. We individually knocked
out every possible JDP and tested the effect on intracellular aggregation
and seeding. DnaJC7 knockout decreased aggregate clearance and increased
intracellular tau seeding. This depended on the ability of the J domain
(JD) of DnaJC7 to stimulate Hsp70 ATPase activity, as JD mutations that
block this interaction abrogated the protective activity.
Disease-associated mutations in the JD and substrate binding site of
DnaJC7 also abolished its protective activity. DnaJC7 thus specifically
regulates tau aggregation in cooperation with Hsp70.