Moesin is an effector of tau-induced actin overstabilization, cell cycle activation, and neurotoxicity in Alzheimer’s disease
Adrian Beckmann,
Paulino Ramirez,
Maria Gamez,
Elias Gonzalez,
Jasmine De Mange,
Kevin F. Bieniek,
William J. Ray,
Bess Frost
Affiliations
Adrian Beckmann
Sam and Ann Barshop Institute for Longevity and Aging Studies, San Antonio, TX, USA; Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, TX, USA; Department of Cell Systems and Anatomy, San Antonio, TX, USA; University of Texas Health San Antonio, San Antonio, TX, USA
Paulino Ramirez
Sam and Ann Barshop Institute for Longevity and Aging Studies, San Antonio, TX, USA; Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, TX, USA; Department of Cell Systems and Anatomy, San Antonio, TX, USA; University of Texas Health San Antonio, San Antonio, TX, USA
Maria Gamez
Sam and Ann Barshop Institute for Longevity and Aging Studies, San Antonio, TX, USA; Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, TX, USA; Department of Cell Systems and Anatomy, San Antonio, TX, USA; University of Texas Health San Antonio, San Antonio, TX, USA
Elias Gonzalez
Sam and Ann Barshop Institute for Longevity and Aging Studies, San Antonio, TX, USA; Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, TX, USA; Department of Cell Systems and Anatomy, San Antonio, TX, USA; University of Texas Health San Antonio, San Antonio, TX, USA
Jasmine De Mange
Sam and Ann Barshop Institute for Longevity and Aging Studies, San Antonio, TX, USA; Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, TX, USA; Department of Cell Systems and Anatomy, San Antonio, TX, USA; University of Texas Health San Antonio, San Antonio, TX, USA
Kevin F. Bieniek
Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, TX, USA; University of Texas Health San Antonio, San Antonio, TX, USA
William J. Ray
The Neurodegeneration Consortium, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Bess Frost
Sam and Ann Barshop Institute for Longevity and Aging Studies, San Antonio, TX, USA; Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, TX, USA; Department of Cell Systems and Anatomy, San Antonio, TX, USA; University of Texas Health San Antonio, San Antonio, TX, USA; Corresponding author
Summary: In Alzheimer’s disease, neurons acquire phenotypes that are also present in various cancers, including aberrant activation of the cell cycle. Unlike cancer, cell cycle activation in post-mitotic neurons is sufficient to induce cell death. 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.” Here we combine network analyses of human Alzheimer’s disease and mouse models of Alzheimer’s disease and primary tauopathy with studies in Drosophila to discover that pathogenic forms of tau drive cell cycle activation by disrupting a cellular program involved in cancer and the epithelial-mesenchymal transition (EMT). Moesin, an EMT driver, is elevated in cells harboring disease-associated phosphotau, over-stabilized actin, and ectopic cell cycle activation. We further find that genetic manipulation of Moesin mediates tau-induced neurodegeneration. Taken together, our study identifies novel parallels between tauopathy and cancer.