Tau interactions with inner nuclear envelope proteins modulates chromatin

Abstract

Abstract/Summary Intracellular re-distribution of the neuronal microtubule associated protein Tau, from the axon into the somatodendritic compartment, is a physiological stress-related event that increases Tau in the soma and enables Tau interactions with the nucleus. Cellular functions of stress-induced Tau-Nucleus interactions are unknown. Combining proximity biotinylation interactomics with chromatin imaging and molecular reconstitution assays, we uncover that physiological Tau interacts with proteins coordinating chromatin at the nuclear membrane, including lamin B receptor, thereby changing their DNA interactions. Accordingly, we find that increasing somatodendritic Tau is sufficient to dysregulate expression of genes in lamin associated domains and transcription factors, collectively leading to an upregulation of stress response pathways and downregulation of cholesterol metabolic genes. These nuclear envelope-related mechanisms suggest that neuronal stress-related somatodendritic Tau missorting can initiate chromatin-related cascades important for early changes in AD and tauopathies.

Affiliated Institutions

• Max Planck Institute of Molecular Cell Biology and Genetics DE
• Charité - Universitätsmedizin Berlin DE
• Epigenomics (Germany) DE
• Leibniz-Forschungsinstitut für Molekulare Pharmakologie DE
• German Center for Neurodegenerative Diseases DE
• Friedrich-Alexander-Universität Erlangen-Nürnberg DE
• University of Edinburgh GB

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