Biology subjects

Franck, M.

Publications and source records attributed to Franck, M..

3 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

Evidence for an energetic trade-off model linking inflammaging and immunosenescence in the US Health and Retirement Study and UK Biobank

Later life is characterized by the development of chronic inflammation, termed inflammaging, alongside changes in immune cell profiles, or immunosenescence. While these features contribute to health risk, they have also been interpreted as adaptive remodeling of the immune system in response to accumulating somatic damage. Here we consider a recently developed theoretical framework to understand these processes as interrelated: the Brain-Body Energy Conservation model of aging. This model views functional declines, such as immunosenescence, as part of an energy conserving response to the rising energy expenditure of inflammaging. This response promotes short term survival against somatic damage at the expense of future health risk. For example, naive T cells, which enhance defense against future infections, decline with age. We find evidence consistent with this model in the US Health and Retirement Study (HRS) and UK Biobank (UKB). TNFR1, a key marker of inflammaging, mediated 10% and 5% of the age-related declines in naive CD4T and CD8T cells respectively in the HRS (n = 8,261). Consistent with an impaired immune response to future infections, TNFR1 also mediated 16% of the age-related increased risk of hospitalization or death from COVID-19 in the UKB (n = 522 hospitalized or died, full sample n = 40,638). GDF15, which is produced in response to metabolic stress and has been found to induce immune tolerance in response to chronic inflammation, mediated 28% of the TNFR1-related COVID-19 health risk, as well as 38% of the age-related increased risk independent of TNFR1.

evolutionary biology↗

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↗