Biology subjects

Bonanomi, D.

Publications and source records attributed to Bonanomi, D..

5 recordsLinked to original sources

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↗

bioRxiv2025

A neurovascular template guides the spatial and functional compartmentalization of the adrenal gland

The vasculature adapts to tissue demands, but whether it can instruct spatial tissue organization remains unclear. In the developing adrenal gland, we uncover a neurovascular mechanism that actively establishes and preserves compartment boundaries between cortex and medulla. Peripheral nerves secrete Semaphorin3C, signaling through PlexinD1 on endothelial cells to locally antagonize VEGF-driven angiogenesis from cortical cells, sculpting distinct vascular domains that guide hormone-producing cells to their correct territories. Disruption of this balance --via denervation or loss of Semaphorin3C-PlexinD1 signaling-- leads to ectopic vascularization of the medulla, which adopts a cortex-like vascular network. This vascular remodeling enables cortical cells invasion of medullary territories, blurring compartment boundaries and triggering a phagocytic macrophage response that reflects pathological hijacking of a postnatal morphogenesis program. Our findings reveal that region-specific vascular scaffolds, shaped by neurovascular cues, serve as instructive templates for organ architecture. Failure of neurovascular signaling can thus trigger a cascade of structural collapse that undermines tissue integrity and homeostasis, driving pathological remodeling.

developmental biology↗

bioRxiv2024

CoPPIs Algorithm: A Tool to Unravel Protein Cooperative Strategies in Pathophysiological Conditions

We present here the Co-expressed Protein-Protein Interactions (CoPPIs) algorithm. In addition to minimizing correlation-causality imbalance and contextualizing PPIs to the investigated systems, it combines PPIs and protein co-expression networks to identify differentially correlated functional modules. To test CoPPIs, we processed a set of proteomic profiles from different brain areas of controls and subjects affected by idiopathic Parkinsons disease or carrying a GBA1 mutation. Its robustness was supported by the extraction of functional modules, related to translation and mitochondria, whose involvement in PD pathogenesis is well documented. Furthermore, the selection of hubs and bottlenecks from the weighted PPI networks provided molecular clues consistent with the PD pathophysiology. Of note, like quantification, the CoPPIs algorithm revealed less variations when comparing disease groups than when comparing diseased and controls. However, correlation and quantification results showed low overlap, suggesting the complementarity of these measures. An observation that opens the way to a new investigation strategy that takes into account not only protein expression, but also the level of coordination among proteins that cooperate to perform a given function.

systems biology↗

bioRxiv2023

Motor nerves direct the development of the sympathetic nervous system

The sympathetic nervous system controls a wide spectrum of bodily functions including operation of vessels, cardiac rhythm, and the "flight or fight response". Sympathetic neurons, which are neural crest-derived, develop in coordination with presynaptic motor nerves extending from the central nervous system (CNS). By using nerve-selective genetic ablations, we revealed that sympathetic ganglia development depends on CNS-derived motor innervation. In the absence of preganglionic motor nerves, trunk sympathetic chain ganglia were fragmented and smaller in size, while cervical ganglia were severely misshapen. Sympathetic neurons were misplaced along sensory fibers and projected towards abnormal paths, in some cases invading the sensory dorsal root ganglia. The misplaced progenitors of sympathoblasts corresponded to the nerve-associated, neural crest-derived Schwann cell precursors (SCPs). Notably, we found that SCPs activate the autonomic marker PHOX2B while migrating along motor nerves towards the region of the dorsal aorta in wildtype embryos, suggesting that SCP differentiate into sympathetic neurons while still nerve-associated in motor-ablated embryos. Ligand-receptor prediction from single cell transcriptomic data coupled with functional studies identified Semaphorin 3A/3F as candidate motor nerve-derived signals influencing neural crest migration along axons. Thus, motor nerves control the placement of sympathoblasts and their subsequent axonal navigation during critical periods of sympathetic chain development.

developmental biology↗

bioRxiv2018

A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling

BackgroundGLI2 encodes for a transcription factor that controls the expression of several genes in the Hedgehog pathway. Mutations in GLI2 have been described as causative of a spectrum of clinical phenotypes, notably holoprosencephaly, hypopituitarism and postaxial polydactyl. Methods: In order to identify causative genetic variant, we performed exome sequencing of a trio from an Italian family with multiple affected individuals presenting clinical phenotypes in the Culler-Jones syndrome spectrum. We performed a series of assays, both in vitro and in ovo (Chicken model) to test the functional properties of GLI2 mutation.\n\nResultsHere we report a novel deletion c.3493delC (p.P1167LfsX52) in the C-terminal activation domain of GLI2, and cell-based functional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling.\n\nConclusionOur results highlight the variable clinical manifestation of GLI2 mutations and emphasize the value of functional characterisation of novel gene variants to assist genetic counselling and diagnosis.

genetics↗