Objectives: Tauopathies are grave neurodegenerative disorders characterized by intraneuronal accumulation and aggregation of the microtubule stabilizer tau. We focus on molecular chaperones due to their innate ability to prevent abnormal aggregation of intracellular proteins. We screened members of the DnaJ family of chaperones to discover their potential as tau modulators. In doing so, we can identify novel therapeutic targets for the treatment of tauopathies.
Methods: Tau overexpressing, stably transfected HeLaC3 cells were used as a cell culture model for AD to analyze the effect of DnaJ chaperones on tau. These cells were transiently transfected with various DnaJs and control vector. Cells were harvested 48 hrs post-transfection for Western blot (WB) analysis.
Results: Several DnaJs modulated tau and phospho-tau levels. In particular, DnaJA1 and DnaJC7 showed contrasting effects on total tau; yet they both potently reduced the major phospho-tau species found in intraneuronal tau aggregates. Moreover, DnaJC7 abrogated phospho-tau and caspase-cleaved tau, disease relevant species, without significantly altering total tau levels.
Conclusions: We found DnaJs that specifically target aberrant tau. Our data suggest that certain DnaJs specifically target unique substrates thereby introducing specificity to the chaperone network. Pharmacological interventions targeting specific DnaJs may provide effective therapeutic strategies diseases involving protein aggregation