Boselli, D. | Search bioRxiv

bioRxiv2025

BoltzGen: Toward Universal Binder Design

We introduce BoltzGen, an all-atom generative model for designing proteins and peptides across all modalities to bind a wide range of biomolecular targets. BoltzGen builds strong structural reasoning capabilities about target-binder interactions into its generative design process. This is achieved by unifying design and structure prediction, resulting in a single model that also reaches state-of-the-art folding performance. BoltzGens generation process can be controlled with a flexible design specification language over covalent bonds, structure constraints, binding sites, and more. We experimentally validate these capabilities in eight diverse design campaigns with functional and affinity readouts across 26 targets. In our experiments, binder modalities span from nanobodies to disulfide-bonded peptides, and targets from disordered proteins to small molecules. In particular, we identify nanobody binders for novel targets with low similarity to proteins with already known bound structures. We release model weights, data, and both inference and training code at: https://github.com/HannesStark/boltzgen.

bioengineering↗

bioRxiv2025

Early endothelial activation at the blood-nerve barrier defines a hallmark of ALS

Vascular defects are common in Amyotrophic Lateral Sclerosis (ALS). The prevailing view is that breakdown of the blood-brain and blood-spinal cord barriers contributes to neurodegeneration. Here, we reveal that selective and early vulnerability of peripheral nerve endothelium --manifested as endothelial cell activation and interlinked blood-nerve barrier dysfunction-- constitutes a core feature of ALS pathogenesis, arising before vascular alterations in the central nervous system (CNS) and motor neuron pathology. Vascular changes in ALS patients have been largely studied in postmortem samples, limiting insight into their onset, causes, and pathogenic role. Surveying diagnostic motor nerve samples from ALS patients across clinical stages, we observed endothelial damage that preceded axonal loss and demyelination, marking vascular dysfunction as an early disease event. Similar ultrastructural abnormalities were detected in pre-symptomatic ALS mouse models (SOD1 and TARDBP mutants). Notably, endothelial cells became dysfunctional even when not carrying mutant TDP-43, indicating they respond to non-cell autonomous disease signals. Transcriptional, histological, and functional analyses revealed that these alterations were largely confined to peripheral nerves, while spinal cord vessels exhibited delayed and more focal changes. Single-cell sequencing identified ALS-susceptible endothelial cell subsets prone to a pro-inflammatory phenotype and impaired blood-nerve barrier function, increasing permeability via the transcellular route. These changes coincided with reactivity of nerve-resident macrophages and neutrophil infiltration. Neutrophil depletion attenuated endothelial activation and barrier leakiness, mitigating axonopathy in ALS mice. Our work unmasks the greater susceptibility of the peripheral nerve vasculature in ALS relative to the CNS. The early activation of peripheral nerve endothelium, combined with its potential reversibility, identifies a therapeutic window and suggests strategies for targeting the vascular-immune axis to protect the motor system.

neuroscience↗