Ecdysone (Ec) signaling pathway activation can block Aβ42 mediated neurodegeneration
Neha Gogia, Lydia C Payton, Matthew Richard Riccetti, Ankita Sarkar
Alzheimer’s disease (AD) is a chronic neurodegenerative condition that affects nearly 44 million people worldwide with no proper early detection methods or cures to date, but promising molecular genetic evidence is arising from studying the development of nervous tissue in model organisms like Drosophila melanogaster. In order to better understand the mechanism, we misexpressed human Aβ42, the causal pathological agent of AD, in the eye of Drosophila. This stable transgenic line results in GMR-GAL4 driven UAS-amyloid-beta (GMR>Aβ42) mediated cell death in the eyes of nearly 100% flies at 29°C. We identified the Ecdysone signaling pathway as a modifier of Aβ42-mediated neurodegeneration. The Ecdysone (Ecd) signaling pathway has been shown to modulate Hippo transcriptional activity in imaginal disc cells. The Ecd coactivator Taiman (Tai) forms a unique transcriptional complex with the Hippo transcription factor Yki, altering expression of canonical Hippo targets and inducing transcription of germline stem cell factors in regions that have already differentiated. We proposed to a) Investigate if the Ecd pathway can trigger cell proliferation machinery through induction of stem cell factors, and b) to investigate if the Ecd pathway can block cell death machinery. Our data suggests that upregulation of the Yki-Tai transcription complex constituents does not induce germ cell-like growth in the GMR domain as is typically seen in Yki hyperactivity, but reduces apoptotic-mediated cell death. We found that Taiman upregulation leads to increased expression of canonical Hippo target Diap1, which subsequently blocks activity of the pro-apoptotic proteins Hid and Caspase-3, rescuing Aβ42 mediated neurodegeneration in our Drosophila eye model. Ecdysone and Hippo signaling pathways have not previously been identified as modifiers of neurodegeneration; our results show that activation of this unique Ecd/Hippo transcriptional program has significant bearings on disease pathology and may serve as a novel protein interaction network for AD therapeutics in the future.
Honors Thesis - Graduate
Madhuri Kango-Singh, Amit Singh
Primary Advisor's Department
Stander Symposium poster
"Ecdysone (Ec) signaling pathway activation can block Aβ42 mediated neurodegeneration" (2017). Stander Symposium Posters. 935.