Tau modulates nuclear integrity, chromatin, and cholesterol synthesis genes via the nuclear envelope

Abstract

Abstract/SummaryThe intracellular re-distribution of the neuronal microtubule-associated protein Tau, from the axon into the somatodendritic compartment, is a physiological stress-related event and occurs early in Alzheimers disease (AD). Nuclear envelope distortions have been linked to the presence and aggregation of pathological Tau near the nucleus in these diseases. How physiologically increased soma Tau levels, enabling Tau interactions with the nucleus, impact nuclear integrity and neuronal physiology is unclear. Combining proximity biotinylation interactomics with chromatin imaging and molecular assays, we show that soluble Tau interacts with proteins coordinating chromatin at the inner nuclear membrane, including lamin B receptor and SUN1. This interaction promotes nuclear envelope invaginations and damage and changes the coordination of DNA at the nuclear lamina. Increasing somatodendritic Tau is sufficient to upregulate the expression of multiple transcription factors implicated in AD pathogenesis and to reduce expression of genes involved in cholesterol biosynthesis, which seem coordinated at lamin associated domains. These nuclear envelope-related mechanisms suggest that physiological, neuronal stress-related somatodendritic Tau missorting can initiate chromatin-related cascades important for early changes in AD and tauopathies.