Biology subjects

Le Gros, M. A.

Publications and source records attributed to Le Gros, M. A..

4 recordsLinked to original sources

bioRxiv2026

Reverse engineering Lewy bodies suggests alpha-synuclein pathology as condensatopathy

Understanding how soluble monomeric alpha-synuclein transitions into pathological alpha-synuclein (Lewy bodies) has remained a central challenge in neurodegeneration. Existing models, largely based on treating cells and animals with pre-formed alpha-synuclein fibrils cannot account for the emergence of the first inclusion without pre-existing seeds. Here, we combine in vitro reconstitutions, computational modeling and a minimal cellular system to show that phase separation of alpha-synuclein with an interacting scaffold can recapitulate Lewy body-like structures. An unbiased proteomics screen, live-cell imaging, correlative light-electron microscopy, and soft X-ray tomography show that Lewy body-like structures are associated with redistribution of actin and membrane-bound organelles, with mitochondria accumulating at their periphery in an actin-dependent manner. Structural analyses further indicate that alpha-synuclein condensates provide local environments in which the insoluble beta-sheets can form. Together, these findings support a seed-independent trajectory from soluble alpha-synuclein through condensation and progressive immobilization to Lewy body-like assemblies and, subsequently, insoluble beta-sheet fibrils. This framework offers a new mechanistic route for understanding the disease progression and promises to guide the design of innovative therapeutic interventions.

neuroscience↗

bioRxiv2025

Decoding acute neuroinflammatory states from the 3D architecture of in vitro microglia

Microglia, core brain immune defenders, rapidly polarize into pro- or anti-inflammatory states that shape neuronal survival during acute brain inflammation. Yet, how these inflammatory states are encoded at the native cellular level remains unclear. While microglial states associate with specific molecular and organelle markers, it is unknown whether their cellular architecture integrates robust metabolic and structural features. Here, we quantitatively decode inflammatory states from the 3D architecture of individual in vitro mouse microglia (BV-2). Using soft X-ray tomography on established BV-2 polarization, we identify coordinated intracellular organization distinguishing homeostatic, pro-inflammatory, and anti-inflammatory cells, including characteristic lipid droplet-endosome architectures. We further link lipid-endosome reorganization with mTORC1 pathway, by functionally implicating sestrin-2 in promoting anti-inflammation. Finally, we resolve the time-dependent remodeling of lipid droplet 3D profiles by their distinct lipidomic composition across inflammatory states. Overall, our work enables deciphering microglia states in disease-relevant models, with potential to ultimately understand brain immunity.

cell biology↗

bioRxiv2022

Extending of imaging volume in soft x-ray tomography

Soft x-ray tomography offers rapid whole single cell imaging with a few tens of nanometers spatial resolution without fixation or labelling. At the moment, this technique is limited to 10 {micro}m thick specimens, such that applications of soft x-ray tomography to large human cells or multicellular specimens are not possible. We have developed a theoretical and experimental framework for soft x-ray tomography to enable extension of imaging volume to 18 {micro}m thick specimens. This approach, based on long depth of field and half-acquisition tomography, is easily applicable to existing full-rotation based microscopes. This opens applications for imaging of large human cells, which are often observed in cancer research and cell to cell interactions.

cell biology↗

bioRxiv2020

Strong intracellular signal inactivation produces sharper and more robust signaling from cell membrane to nucleus

For a chemical signal to propagate across a cell, it must navigate a tortuous environment involving a variety of organelle barriers. In this work we study mathematical models for a basic chemical signal, the arrival times at the nuclear membrane of proteins that are activated at the cell membrane and diffuse throughout the cytosol. Organelle surfaces within human B cells are reconstructed from soft X-ray tomographic images, and modeled as reflecting barriers to the molecules diffusion. We show that signal inactivation sharpens signals, reducing variability in the arrival time at the nuclear membrane. Inactivation can also compensate for an observed slowdown in signal propagation induced by the presence of organelle barriers, leading to arrival times at the nuclear membrane that are comparable to models in which the cytosol is treated as an open, empty region. In the limit of strong signal inactivation this is achieved by filtering out molecules that traverse non-geodesic paths.

biophysics↗