Tau-mediated axonal degeneration is prevented by activation of the WldSpathway

Tauopathy is characterised by neuronal dysfunction and degeneration occurring as a result of changes to the microtubule associated protein tau. The neuronal changes evident in Tauopathy bear striking morphological resemblance to those reported in models of Wallerian degeneration. The mechanisms underpinning Wallerian degeneration are not fully understood although it can be delayed by the expression of the slow Wallerian degeneration (Wld S ) protein, which has also been demonstrated to delay axonal degeneration in some models of neurodegenerative disease. Given the morphological similarities between tauopathy and Wallerian degeneration, this study investigated whether tau-mediated phenotypes can be modulated by expression of Wld S . In a Drosophila model of tauopathy in which expression of human Tau protein (hTau 0N3R ) leads to progressive age-dependent phenotypes, activation of the pathway downstream of Wld S completely suppressed tau-mediated degeneration. This protective effect was evident even if the pathway downstream of Wld S was activated several weeks after hTau-mediated degeneration had become established. In contrast, Wld S expression without activation of the downstream protective pathway did not rescue tau-mediated degeneration in adults or improve tau-mediated neuronal dysfunction including deficits in axonal transport, synaptic alterations and locomotor behaviour in hTau 0N3R –expressing larvae. This collectively implies that the pathway mediating the protective effect of Wld S intersects with the mechanism(s) of degeneration initiated by hTau and can effectively halt tau-mediated degeneration at both early and late stages. Understanding the mechanisms underpinning this protection could identify much-needed disease-modifying targets for tauopathies.