Asadzadeh, J., Ruchti, E., Jiao, W., Limoni, G., MacLachlan, C., Small, S.A., Knott, G., Santa-Maria, I., McCabe, B.D. (2022). Retromer deficiency in Tauopathy models enhances the truncation and toxicity of Tau. Nat. Commun. 13(1): 5049.
FlyBase ID
FBrf0254347
Publication Type
Research paper
Abstract
Alteration of the levels, localization or post-translational processing of the microtubule associated protein Tau is associated with many neurodegenerative disorders. Here we develop adult-onset models for human Tau (hTau) toxicity in Drosophila that enable age-dependent quantitative measurement of central nervous system synapse loss and axonal degeneration, in addition to effects upon lifespan, to facilitate evaluation of factors that may contribute to Tau-dependent neurodegeneration. Using these models, we interrogate the interaction of hTau with the retromer complex, an evolutionarily conserved cargo-sorting protein assembly, whose reduced activity has been associated with both Parkinson's and late onset Alzheimer's disease. We reveal that reduction of retromer activity induces a potent enhancement of hTau toxicity upon synapse loss, axon retraction and lifespan through a specific increase in the production of a C-terminal truncated isoform of hTau. Our data establish a molecular and subcellular mechanism necessary and sufficient for the depletion of retromer activity to exacerbate Tau-dependent neurodegeneration.
