Alzheimer’s disease-associatedTM2Dgenes regulate Notch signaling and neuronal function inDrosophila

AbstractTM2 domain containing (TM2D) proteins are conserved in metazoans and encoded by three separate genes in each species. Rare variants inTM2D3are associated with Alzheimer’s disease (AD) and its fly orthologalmondexis required for embryonic Notch signaling. However, the functions of this gene family remain elusive. We knocked-out all threeTM2Dgenes (almondex, CG11103/amaretto,CG10795/biscotti) inDrosophilaand found that they share the same maternal-effect neurogenic defect. Triple null animals are not phenotypically worse than single nulls, suggesting these genes function together. Overexpression of the most conserved region of the TM2D proteins acts as a potent inhibitor of Notch signaling at the γ-secretase cleavage step. Lastly, Almondex is detected in the brain and its loss causes shortened lifespan accompanied by progressive electrophysiological defects. The functional links between all threeTM2Dgenes are likely to be evolutionarily conserved, suggesting that this entire gene family may be involved in AD.