Neurodegenerative dementias collectively known as Tauopathies involve aberrant 
phosphorylation and aggregation of the neuronal protein Tau. The largely 
neuronal 14-3-3 proteins are also elevated in the central nervous system (CNS) 
and cerebrospinal fluid of Tauopathy patients, suggesting functional linkage. We 
use the simplicity and genetic facility of the Drosophila system to investigate 
in vivo whether 14-3-3s are causal or synergistic with Tau accumulation in 
precipitating pathogenesis. Proteomic, biochemical and genetic evidence 
demonstrate that both Drosophila 14-3-3 proteins interact with human wild-type 
and mutant Tau on multiple sites irrespective of their phosphorylation state. 
14-3-3 dimers regulate steady-state phosphorylation of both wild-type and the 
R406W mutant Tau, but they are not essential for toxicity of either variant. 
Moreover, 14-3-3 elevation itself is not pathogenic, but recruitment of dimers 
on accumulating wild-type Tau increases its steady-state levels ostensibly by 
occluding access to proteases in a phosphorylation-dependent manner. In 
contrast, the R406W mutant, which lacks a putative 14-3-3 binding site, responds 
differentially to elevation of each 14-3-3 isoform. Although excess 14-3-3ζ 
stabilizes the mutant protein, elevated D14-3-3ɛ has a destabilizing effect 
probably because of altered 14-3-3 dimer composition. Our collective data 
demonstrate the complexity of 14-3-3/Tau interactions in vivo and suggest that 
14-3-3 attenuation is not appropriate ameliorative treatment of Tauopathies. 
Finally, we suggest that 'bystander' 14-3-3s are recruited by accumulating Tau 
with the consequences depending on the composition of available dimers within 
particular neurons and the Tau variant.