Abstract
Tauopathies are neurodegenerative diseases characterized by the presence of aggregates of abnormally phosphorylated Tau. Deciphering the pathophysiological mechanisms that lead from the alteration of Tau biology to neuronal death depends on the identification of Tau cellular partners. Combining genetic and transcriptomic analyses in Drosophila, we identified 77 new modulators of human Tau-induced toxicity, bringing to 301 the number of Tau genetic interactors identified so far in flies. Network analysis showed that 229 of these genetic modulators constitute a connected network. The addition of 77 new genes strengthened the network structure, increased the intergenic connectivity and brought up key hubs with high connectivities, namely Src64B/FYN, Src42A/FRK, kuz/ADAM10, heph/PTBP1, scrib/SCRIB, and Cam/CALM3. Interestingly, we established for the first time a genetic link between Tau-induced toxicity and ADAM10, a recognized Alzheimer Disease protective factor. In addition, our data support the importance of the presynaptic compartment in mediating Tau toxicity.
Highlights
The microtubule-associated protein Tau, encoded by the MAPT gene, has been associated with multiple neurodegenerative disorders, including Alzheimer’s disease (AD), fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick’s disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP)
We found that genetic manipulations of 59 novel genes robustly modified Tau-induced neurodegeneration in Drosophila (Table 1, Supplementary Figure S1, and Supplementary Table S2)
Consistent with presynaptic Tau-induced toxicity, we identified several genes known to be involved in neurotransmitter release from synaptic vesicles, including complexin, Rab14, Ryanodine receptor (RyR), and scribble
Summary
The microtubule-associated protein Tau, encoded by the MAPT gene, has been associated with multiple neurodegenerative disorders, including Alzheimer’s disease (AD), fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick’s disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). These disorders, collectively known as tauopathies, are characterized by the accumulation of intracellular filamentous inclusions composed of aberrantly post-translationally modified Tau proteins. In addition to its microtubule-stabilizing properties, recent studies have highlighted new roles of Tau in different neuronal compartments, such as DNA/RNA protection, maintenance of the integrity of genomic DNA, stability of pericentromeric heterochromatin, regulation of neuronal activity, and synaptic plasticity (Sotiropoulos et al, 2017). Several other posttranslational modifications of Tau and protease-mediated cleavage have been reported and may Abbreviations: AD, Alzheimer’s disease; LoF o/e, observed/expected ratio of loss-of-function variations
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
