RT Journal Article SR Electronic T1 Differential Effects of Tau on the Integrity and Function of Neurons Essential for Learning in Drosophila JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 464 OP 477 DO 10.1523/JNEUROSCI.1490-09.2010 VO 30 IS 2 A1 Stylianos Kosmidis A1 Sofia Grammenoudi A1 Katerina Papanikolopoulou A1 Efthimios M. C. Skoulakis YR 2010 UL http://www.jneurosci.org/content/30/2/464.abstract AB Tauopathies are a heterogeneous group of neurodegenerative dementias involving perturbations in the levels, phosphorylation, or mutations of the microtubule-binding protein Tau. The heterogeneous pathology in humans and model organisms suggests differential susceptibility of neuronal types to wild-type (WT) and mutant Tau. WT and mutant human Tau-encoding transgenes expressed pan-neuronally in the Drosophila CNS yielded specific and differential toxicity in the embryonic neuroblasts that generate the mushroom body (MB) neurons, suggesting cell type-specific effects of Tau in the CNS. Frontotemporal dementia with parkinsonism-17-linked mutant isoforms were significantly less toxic in MB development. Tau hyperphosphorylation was essential for these MB aberrations, and we identified two novel putative phosphorylation sites, Ser238 and Thr245, on WT hTau essential for its toxic effects on MB integrity. Significantly, blocking putative Ser238 and Thr245 phosphorylation yielded animals with apparently structurally normal but profoundly dysfunctional MBs, because animals accumulating this mutant protein exhibited strongly impaired associative learning. Interestingly, the mutant protein was hyperphosphorylated at epitopes typically associated with toxicity and neurodegeneration, such as AT8, AT100, and the Par-1 targets Ser262 and Ser356, suggesting that these sites in the context of adult intact MBs mediate dysfunction and occupation of these sites may precede the toxicity-associated Ser238 and Thr245 phosphorylation. The data support the notion that phosphorylation at particular sites rather than hyperphosphorylation per se mediates toxicity or dysfunction in a cell type-specific manner.