Biology subjects

Diez, L.

Publications and source records attributed to Diez, L..

5 recordsLinked to original sources

bioRxiv2026

Inhomogeneous Tau polymerization, core-shell organization, and seed formation during Tau condensate aging

Several proteins aggregating in neurodegenerative diseases spontaneously segregate into liquid condensates, which can catalyze protein aggregation. How liquid-solid transitions are catalyzed in the confined condensate volume is not clear. For the microtubule associated protein Tau, aggregating intra-neuronally in Alzheimer's disease, we show that, during maturation, Tau condensates convert into elastic protein networks, accompanied by inhomogeneous polymerization of the condensate interior and the formation of high-density nodes and a 'shell'. During condensation, Tau molecules extend, favoring intermolecular interactions and priming for progressive parallel Tau arrangement that can enable amyloid-like Tau oligomerization. In cells, aged condensates seed small Tau clusters in cytosol and at the nuclear envelope, precursors of larger aggregates. By bridging molecular to condensate level, we present mechanistic insight into how Tau condensates evolve into pathological, beta-structure containing seeds. The interior of aged Tau condensates remains accessible for smaller molecules, providing the opportunity to molecularly target Tau seed formation inside condensates.

biochemistry↗

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↗

bioRxiv2024

14-3-3 binding regulates Tau assembly and microtubule association.

The microtubule (MT) association of protein Tau is decreased upon phosphorylation. Increased levels of phosphorylated Tau in the cytosol pose the risk of pathological aggregation, as observed in neurodegenerative diseases. We show that binding of 14-3-3{zeta} enhances cytosolic Tau solubility by promoting phosphorylated Tau removal from MTs, while simultaneously inhibiting Tau aggregation both directly and indirectly via suppression of condensate formation. These 14-3-3{zeta} activities depend on site-specific binding of 14-3-3 to Tau phosphorylated at S214 and S324. At sub-stoichiometric 14-3-3{zeta} concentrations, or in the presence of other 14-3-3{zeta} binding partners, multivalent electrostatic interactions promote Tau:14-3-3{zeta} co-condensation, offering a phosphorylation-independent mode of Tau-14-3-3{zeta} interactions. Given the high abundance of 14-3-3 proteins in the brain, 14-3-3 binding could provide efficient multi-modal chaperoning activity for Tau in the healthy brain and be important for preventing Tau aggregation in disease.

biochemistry↗

bioRxiv2024

Autoimmune antibody-induced neuronal hyperactivity triggers pathological Tau in IgLON5 disease

Anti-IgLON5 disease is an autoimmune disease, in which autoantibodies (AABs) against the neuronal cell surface protein IgLON5 lead to profound brain dysfunction and Tau pathology. How -IgLON5 AABs cause neuronal Tau protein pathology and neurodegeneration remains unclear. We find that patient-derived -IgLON5 AABs cluster IgLON5 proteins with other cell surface proteins, leading to neuronal hyperactivity that triggers pathological Tau missorting and phosphorylation, typically observed early in Tau-related neurodegenerative diseases. In wildtype mice, -IgLON5 AABs induce hippocampal Tau phosphorylation and neuroinflammatory responses. Our findings establish a causal link between the -IgLON5 AABs and Tau pathology in anti-IgLON5 disease patients, and highlight the role of neuronal hyperactivity as a disease-overarching driver of Tau pathology and provide a potential target for therapeutic intervention. Teaser-IgLON5 autoantibodies induce clustering of neuronal cell surface proteins, leading to acute neuronal hyperactivity and Tau missorting.

neuroscience↗

bioRxiv2022

Biomolecular Tau condensation is linked to Tau accumulation at the nuclear envelope

Biomolecular condensation of the neuronal microtubule-associated protein Tau (MAPT) can be induced by coacervation with polyanions like RNA, or by molecular crowding. Tau condensates have been linked to both functional microtubule binding and pathological aggregation in neurodegenerative diseases. We find that molecular crowding and coacervation with RNA, likely coexisting in the cytosol, synergize to enable Tau condensation at physiological buffer conditions and produce condensates with a strong affinity to charged surfaces. During condensate-mediated microtubule polymerization, this synergy enhances bundling and spatially arranges microtubules. We further show that different Tau condensates efficiently induce pathological Tau in cells, including small accumulations at the nuclear envelope that correlate with nucleocytoplasmic transport deficits. Fluorescent lifetime imaging reveals different molecular packing densities of Tau in cellular accumulations, and a condensate-like density for nuclear envelope Tau. These findings suggest that a complex interplay between interaction partners, post-translational modifications, and molecular crowding regulates the formation and function of Tau condensates. Conditions leading to prolonged existence of Tau condensates may induce the formation of seeding-competent Tau and lead to distinct cellular Tau accumulations.

molecular biology↗