Bordier, C. | bioRxiv Science

bioRxiv2025

Tau interactions with inner nuclear envelope proteins modulates chromatin

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.

neuroscience↗

bioRxiv2017

Disrupted modular organization of primary sensory brain areas in schizophrenics

Abnormal brain resting-state functional connectivity has been consistently observed in patients affected by Schizophrenia (SCZ) using functional MRI and other neuroimaging methods. Graph theoretical methods provide a framework to investigate these defective functional interactions and their effects on the modular organization of brain connectivity networks. A few studies have shown abnormal distribution of connectivity within and between functional modules, an indication of imbalanced functional segregation ad integration in SCZ patients. However, no major alterations in the modular structure of functional connectivity networks in patients have been reported, and unambiguous identification of the neural substrates involved remains elusive. Recently, it has been demonstrated that current modularity analysis methods suffer from a fundamental and severe resolution limit, as they fail to detect features that are smaller than a scale determined by the size of the entire connectivity network. This resolution limit is likely to have hampered the ability to resolve differences between patients and controls in previous cross-sectional studies. Here, we apply a novel, resolution limit-free approach to study the modular organization of resting state functional connectivity networks in a large cohort of SCZ patients, and in matched healthy controls. Leveraging these important methodological advances, we find new evidence of substantial fragmentation and reorganization involving primary sensory, auditory and visual areas in SCZ patients. Conversely, frontal and prefrontal areas, typically associated with higher cognitive functions, appear to be largely unaffected, with changes selectively involving language and speech processing areas. Our findings provide support to the hypothesis that cognitive dysfunction in SCZ may arise from deficits occurring already at early stages of sensory processing.

neuroscience↗