Biology subjects

Badaloni, A.

Publications and source records attributed to Badaloni, A..

4 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↗

bioRxiv2025

Model-independent reorganization of translation in TDP-43 Amyotrophic Lateral Sclerosis

The RNA-binding protein TDP-43 is a major contributor and a pathological hallmark of Amyotrophic Lateral Sclerosis (ALS), yet how TDP-43 dysregulation mechanistically alters protein synthesis across neuronal compartments and disease models remains unclear. Here, we dissected TDP-43-driven translational alterations in both in vitro and in vivo TDP-43 models of ALS. Through ribosome and polysome profiling, computational, and biochemical analyses, we observed robust TDP-43-associated translational remodelling at cellular and subcellular resolution. Our findings reveal a conserved mechanism across models, characterized by enhanced ribosome recruitment on polysomes, elongation impairment, axonal downregulation and instability of TDP-43 target mRNAs and redistribution toward non-target transcripts. Notably, TDP-43 dysregulation alters ribosome dynamics and selectively impairs translation of TDP-43 target mRNAs, whilst favouring the translation of other transcripts. This process reflects a compensatory but maladaptive response to TDP-43-induced mRNA destabilization. Together, these data demonstrate that alterations in TDP-43 disrupts neuronal proteostasis through ribosome reorganization and loss of mRNA homeostasis, providing a unifying mechanistic framework for translational imbalance in ALS and revealing early molecular events that may underlie motor neuron vulnerability.

molecular biology↗

bioRxiv2017

Zfp423, A Joubert Syndrome Gene, Is A Domain-Specific Regulator Of Cell Cycle Progression, DNA Damage Response And Purkinje Cell Development In The Cerebellar Primordium

Neurogenesis is a tightly regulated process whose success depends on the ability to balance the expansion/maintenance of an undifferentiated neural progenitor pool with the precisely timed birth of sequential generations of neurons. The Zfp423 gene encodes a 30-Zn-finger transcription factor (TF) that acts as a scaffold in the assembly of complex transcriptional and cellular machineries regulating neural development. While null mutants for Zfp423 feature a severe cerebellar hypoplasia, the underlying mechanism is only partially characterized. Mutations of the human ortholog ZNF423 have been identified in patients carrying cerebellar vermis hypoplasia (CVH) or Joubert Syndrome (JS), associated with other signs of classical ciliopathy outside the central nervous system (CNS). ZNF423 also plays a role in the DNA damage response (DDR). To further characterize the role of ZFP423 in cerebellar neurogenesis, with a focus on Purkinje cells (PC) development, we analyzed two previously undescribed mutant mouse lines carrying allelic in-frame deletions of the corresponding gene, selectively affecting two functionally characterized protein-protein interaction domains, affecting zinc (Zn) fingers 9-20 or 28-30. Some phenotypic defects are allele specific: Zfp423{Delta}9-20/{Delta}9-20 mutants exhibit a depletion of the OLIG2+ PC progenitor pool in the cerebellar ventricular zone (VZ). In these mutants, M-phase progenitors display changes in spindle orientation indicative of a precocious switch from symmetric to asymmetric cell division. Conversely, the Zfp423{Delta}28-30/{Delta}28-30 primordium displays a sharp decrease in the expression of PC differentiation markers, including CORL2, despite an abundance of cycling PC progenitors. Moreover, and importantly, in both mutants VZ progenitor cell cycle progression is remarkably affected, and factors involved in the DDR are substantially upregulated in the VZ and in postmitotic precursors alike. Our in vivo evidence sheds light on the domain-specific roles played by ZFP423 in different aspects of PC progenitor development, and at the same time supports the emerging notion that an impaired DNA damage response may be a key factor in the pathogenesis of JS and other ciliopathies.

neuroscience↗