Examining the vulnerability of adult neuron subtypes to tau-mediated toxicity in Drosophila

Selective vulnerability of nerve cells is a feature of neurodegenerative disease. To date, animal models have been limited to examining pathogenic protein expression in broad or heterogeneous neuronal populations. Consequently, noted pathological hallmarks represent an average of disease phenotypes over multiple neuron types, rather than exact measures of individual responses. Here we targeted gene expression to small, precisely defined and homogenous neuronal populations in the Drosophila melanogaster central nervous system (CNS), allowing dissection of selective vulnerability of single types of neurons with single-neuron resolution. Using cellular degeneration as a readout for vulnerability, we found while all neurons were affected by tau some neuron types were more affected (vulnerable) than others (resilient). The tau-mediated pathogenic effects fell on a spectrum, demonstrating that neurons in the fly CNS are differentially vulnerable to tau pathology. Mechanistically, total tau levels did not correlate with vulnerability; rather, the best correlatives of degeneration were significant age-dependent increases in phospho-tau levels in the same neuron type, and tau mislocalisation into dendrites. Lastly, we found that tau phosphorylation in vulnerable neuron types correlated with downstream vesicular and mitochondrial trafficking defects. However, all vulnerable neuron types did not show the same pattern, suggesting multiple paths to degeneration. Beyond highlighting the heterogeneity of neuronal responses to tau in determining vulnerability, this work provides a new, high-resolution, tractable model for studying the age-dependent effects of tau, or any pathogenic protein, on postmitotic neurons with sub-cellular resolution.