Aggregates of the microtubule-associated protein Tau are neuropathological hallmark lesions in Alzheimer's disease (AD) and related primary tauopathies. In addition, Tau is genetically implicated in a number of human neurodegenerative disorders including frontotemporal dementia (FTD) and Parkinson's disease (PD). The exact mechanism by which Tau exerts its neurotoxicity is incompletely understood. Here, we give an overview of how studies using the genetic model organism Drosophila over the past decade have contributed to the molecular understanding of Tau neurotoxicity. We compare the different available readouts for Tau neurotoxicity in flies and review the molecular pathways in which Tau has been implicated. Finally, we emphasize that the integration of genome-wide approaches in human or mice with high-throughput genetic validation in Drosophila is a fruitful approach. 1. Introduction For more than a century, the fruit fly Drosophila has been used to unravel major biological questions. The fruit fly has played crucial roles in deciphering various developmental signaling cascades such as the Notch, Wingless, and Hedgehog pathways. In addition, studies using Drosophila have contributed to a wide range of topics in neurobiology including neurodevelopment, behavior, circadian rhythms, learning and memory, synaptic transmission, and neurodegeneration [1, 2]. Since most basic molecular and cell biological mechanisms are conserved between humans and Drosophila and since ~70% of all human disease genes have an evolutionary conserved fly homolog, studies in flies have also provided valuable insights into the biology of human disease [3]. During the last decade, Drosophila has gained attention as a model system for common human neurodegenerative brain disorders [4]. In general, these models are based on the misexpression of human proteins such as α-synuclein [5], Tau [6, 7], and TDP-43 [8] that are present in the neuropathological hallmark lesions of patients with Parkinson’s disease (PD), Alzheimer’s disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis. Interestingly, expression of these proteins in flies results in neurotoxicity and the underlying molecular mechanisms appear to be largely protein- or disease-specific suggesting that this approach is useful. Here, we review the contribution of Drosophila to the molecular understanding of Tau neurotoxicity, a central player in the AD-FTD spectrum of disorders [9]. We give a brief overview of the most commonly used genetic tools in Drosophila and summarize the different available Tau
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