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Another new preprint from the Frost lab!

The project was inspired by multiple observations that neurons in human Alzheimer's disease acquire phenotypes that are also present in various cancers: cytoskeletal over-stabilization, nuclear pleomorphisms, decondensation of constitutive heterochromatin, transposable element activation, and aberrant activation of the cell cycle. While cell cycle activation drives tumor formation in the context of cancer, activation of the cell cycle in post-mitotic neurons is sufficient to induce neurodegeneration. Multiple lines of evidence suggest that abortive cell cycle activation is a consequence of pathogenic forms of tau, a protein that drives neurodegeneration in Alzheimer’s disease and related tauopathies. We combined network analysis of human Alzheimer’s disease and mouse tauopathy with mechanistic studies in Drosophila to discover that pathogenic forms of tau drive abortive cell cycle activation by disrupting the cellular program that maintains neuronal identity. Mechanistically, we identify Moesin, a prognostic biomarker for cancer and mediator of the epithelial-mesenchymal transition (EMT), as a major effector of tau-induced neurotoxicity. We find that activated neuronal Moesin acts through the actin cytoskeleton to dysregulate the cellular program that maintains neuronal identity. Our findings converge with the NIA’s AMP-AD consortium, who have recently nominated Moesin as a drug target for Alzheimer’s disease based on genomic and proteomic data from human Alzheimer’s disease samples.


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