Prefoldin 5 is a microtubule-associated protein that suppresses Tau-aggregation and neurotoxicity

Tauopathies represent a major class of neurodegenerative disorders associated with intracellular aggregates of the microtubule-associated protein Tau. To identify molecular modulators of Tau toxicity, we used a genetic screen to identify protein chaperones whose RNAi-mediated knockdown could modulate hTau^V337M-induced eye-ommatidial degeneration inDrosophila. This screen identified the Prefoldins Pfdn5 and Pfdn6 as strong modifiers of hTau^V337Mcytotoxicity. Consistent with the known function of Pfdn as a cotranslational chaperone for tubulin,Pfdn5mutants showed substantially reduced levels of tubulin monomer. However, additional microtubule-related functions were indicated by the robust unexpected association of Pfdn5 with axonal microtubulesin vivo,as well as binding with stabilized microtubules in biochemical assays. Loss of Pfdn5 resulted in neuromuscular junctions (NMJ) defects similar to those previously described in hTau-expressing flies: namely, increased supernumerary boutons and fewer microtubule loops within mature presynaptic boutons. Significantly, synaptic phenotypes caused by hTau^V337Moverexpression were also strongly enhanced in aPfdn5mutant background. Consistent with a role in modulating Tau toxicity, not only did loss ofPfdn5result in increased accumulations of Tau-aggregates in hTau^V337Mexpressing neurons, but also neuronal overexpression of Prefoldin strikingly ameliorated age-dependent neurodegeneration and memory deficits induced by pathological hTau. Together, these and other observations described herein: (a) provide new insight into Prefoldin-microtubule interactions; (b) point to essential posttranslational roles for Pfdn5 in controlling Tau-toxicityin vivo; and (c) demonstrate that Pfdn5 overexpression is sufficient to restrict Tau-induced neurodegeneration.