Biology subjects

Pandolfo, M.

Publications and source records attributed to Pandolfo, M..

6 recordsLinked to original sources

bioRxiv2026

Microglia from Friedreich Ataxia patients are intrinsically primed for neuroinflammation

Friedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by progressive loss of cerebellar and proprioceptive neurons that control movement and coordination. In most patients, FRDA is caused by homozygous GAA trinucleotide repeat expansions in the first intron of the frataxin (FXN) gene, resulting in reduced expression of frataxin, a mitochondrial protein essential for biogenesis of iron-sulfur clusters and mitochondrial function. Although recent therapeutic advances have provided modest clinical benefit, effective disease-modifying treatments remain lacking. Increasing evidence indicates that microglial cell dysfunction contributes to FRDA pathogenesis, highlighting these cells as potential therapeutic targets. However, the molecular mechanisms underlying FXN-deficient microglial dysfunction remain poorly understood. Here, we show that microglia generated from FRDA patient-derived iPSCs exhibit a cell-autonomous pro-inflammatory phenotype in the absence of exogenous inflammatory stimuli. This phenotype is characterized by coordinated activation of immune transcriptional programs, dysregulated secretion of neuroinflammatory proteins, impaired autophagy-lysosomal function, and activation of inflammasomes pathways involving NLRP2 and NLRP3. These findings demonstrate that FXN deficiency is sufficient to induce intrinsic microglial activation and identify molecular pathways that may represent attractive targets for future FRDA therapies.

neuroscience↗

bioRxiv2026

Friedreich ataxia transcriptomic dysregulation and identification of cell type-specific biomarkers: A systematic review and meta-analysis

Friedreich ataxia (FRDA) is a progressive multisystem neurodegenerative disease mostly caused by a homozygous GAA repeat expansion in the FXN gene, leading to deficiency of the protein frataxin. Despite ubiquitous frataxin expression, FRDA pathology is tissue-specific, disproportionately affecting dorsal root ganglia sensory neurons, dentate nuclei of the cerebellum, corticospinal tracts and cardiomyocytes. The molecular basis for this selective vulnerability remains unresolved, suggesting that cell-type specific responses to frataxin deficiency shape disease susceptibility. This incomplete understanding is compounded by the lack of molecular biomarkers that capture FRDA biology beyond frataxin deficiency, thereby limiting therapeutic development and evaluation. Here, we integrated all available human bulk RNA-seq datasets in FRDA (23 datasets across 10 cell types), spanning disease-related (cardiomyocytes, sensory neurons) and relatively FRDA-spared cell types (fibroblasts, lymphoblastoid cells) under a unified analytical framework to identify transcriptional dysregulation underlying selective vulnerability and candidate biomarkers. Meta-analysis revealed recurrent transcriptional perturbations beyond FXN, involving long non-coding RNAs, translational control and cytoskeletal organisation. While shared transcriptional themes were observed, the specific biological programmes engaged were strongly cell-type dependent. The top candidate biomarkers, MYH14, MEG9, and MEG8 showed preferential upregulation in disease-relevant cell types including sensory neurons and cardiomyocytes, supporting their potential relevance to selective vulnerability. Therapeutic responsiveness to these candidates were assessed across RNA-seq datasets from FRDA models exposed to diverse therapeutic strategies, including epigenetic modulation and FXN-targeting approaches, revealing that transcriptional alterations in FRDA are pharmacologically modifiable. To facilitate transparent exploration and reuse of these findings, we developed an interactive FRDA Transcriptomic Atlas, providing a community-accessible resource for investigating gene and pathway-level dysregulation across FRDA studies: https://marniemaddock.github.io/FRDATranscriptomicAtlas/. Together, these findings implicate cell type specific transcriptional programs as potential drivers of selective vulnerability and establish a framework for prioritising biomarkers in FRDA. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/712785v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@26138org.highwire.dtl.DTLVardef@3cbc27org.highwire.dtl.DTLVardef@164dbf5org.highwire.dtl.DTLVardef@a4b59d_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Some like it hot: efficiency of the Type 3 Secretion System and activation of plant defenses have multiple thermosensitive behaviors in the Pseudomonas syringae complex

The Pseudomonas syringae complex is an important group of ubiquitous bacteria containing plant pathogenic strains of which many cause damage and economic losses to a wide range of crops. Efforts to elucidate the determinants of host range have focused on the repertoires of effectors in the Type 3 Secretion System (T3SS). However, recently, we showed that the inability of a P. syringae pv. actinidiae strain to trigger an hypersensitive response (HR) in A. thaliana is due to an inefficient T3SS and not to the absence of a recognized effector. In this context, we compared the efficiency of the T3SS of several P. syringae strains belonging to different phylogroups. Through statistical analysis, we assessed the temporal dynamics of the induction of ion leakage, an HR indicator, in A. thaliana. We revealed that PtoDC3000 avrB and PmaM6 avrB consistently triggered a strong HR while other strains induced it at significantly different intensities depending on temperature. Among thermosensitive strains, both low and warm temperature-dependencies for T3SS efficiency were observed, irrespective of the in-vitro growth optimum of the strains. Surprisingly, differences were also observed among quasi-clonal strains. These results reveal a strong, strain-specific regulatory role of temperature in effector injection and reinforce the importance of environmental factors in the outcome of plant-bacteria interactions. Moreover, this work highlights the need to study bacterial virulence for a broader set of strains beyond model strains, such as PtoDC3000, that are not representative of the whole P. syringae complex.

microbiology↗

bioRxiv2022

MetaPhage: an automated pipeline for analyzing, annotating, and classifying bacteriophages in metagenomics sequencing data.

In the last decades, a great interest has emerged in the study and characterisation of the microbiota, especially the human gut microbiota, demonstrating that commensal microorganisms play a pivotal role in normal anatomical development and physiological function of the human body. To better understand the complex bacterial dynamics that characterize different environments, bacteriophage predation and gene transfer need to be considered as well, as they are important factors that may contribute to controlling the density, diversity, and network interactions among bacterial communities. To date, a variety of bacteriophage identification tools have been developed, differing on phage mining strategies, input files requested and results produced; however, new users approaching the bacteriophage analysis might struggle in untangling the variety of methods and comparing the different results produced. Here we present MetaPhage, a comprehensive reads-to-report pipeline that streamlines the use of multiple miners and generates an exhaustive report to both summarize and visualize the key findings and to enable further exploration of specific results with interactive filterable tables. The pipeline is implemented in Nextflow, a widely adopted workflow manager, that enables an optimized parallelization of the tasks on different premises, from local server to the cloud, and ensures reproducible results using containerized packages. MetaPhage is designed to allow scalability, reproducibility and to be easily expanded with new miners and methods, in a field that is constantly expanding. MetaPhage is freely available under a GPL-3.0 license at https://github.com/MattiaPandolfoVR/MetaPhage.

bioinformatics↗

bioRxiv2019

Induced pluripotent stem cell-derived primary proprioceptive neurons as Friedreich ataxia cell model

Human induced pluripotent stem cells (iPSCs) are used to generate models of human diseases that recapitulate the pathogenic process as it occurs in affected cells. Many differentiated cell types can currently be obtained from iPSCs, but no validated protocol is yet available to specifically generate primary proprioceptive neurons. Proprioceptors are affected in a number of genetic and acquired diseases, including Friedreich ataxia (FRDA).\n\nFRDA is a recessive neurodegenerative and systemic disease due to epigenetic suppression of frataxin (FXN) expression caused by the presence of expanded GAA repeats at the FXN locus. The most characteristic early neuropathologic finding in FRDA is the loss of large primary proprioceptive neurons in the dorsal root ganglia (DRGs), with associated loss of large myelinated fibers in the dorsal roots and in the posterior columns of the spinal cord. Both a developmental deficit and progressive neurodegeneration are thought to underlie the loss of proprioceptors in FRDA, though the relative contribution of these two components is unclear. The basis of the high specific vulnerability of proprioceptors in FRDA is also unknown. In order to address these open questions about FRDA pathogenesis and at the same time develop a cell model that can be applied to other conditions primarily affecting proprioceptors, we set up a protocol to differentiate iPSCs into primary proprioceptive neurons. We modified the dual-SMAD inhibition/WNT activation protocol, previously used to generate nociceptor-enriched cultures of primary sensory neurons from iPSCs, to favor instead the generation of proprioceptors. We succeeded in substantially enriching iPSC-derived primary sensory neuron cultures in proprioceptors, largely exceeding the proportion normally represented by these cells in dorsal root ganglia. We also showed that almost pure populations of proprioceptors can be purified from these cultures by fluorescence-activated cell sorting. Finally, we demonstrated that iPSCs from a FRDA patient can generate normal appearing proprioceptors but have subtle differentiation deficits and more limited survival.

neuroscience↗

bioRxiv2017

Oxidative stress and loss of Fe-S proteins in Friedreich ataxia induced pluripotent stem cell-derived PSNs can be reversed by restoring FXN expression with a benzamide HDAC inhibitor.

Epigenetic suppression of frataxin (FXN) expression caused by the presence of expanded GAA repeats at the FXN locus is the key pathogenic event in Friedreich ataxia (FRDA), a recessive neurodegenerative and systemic disease. FXN is involved in iron-sulfur (Fe-S) cluster biogenesis in mitochondria, its deficiency causes multiple Fe-S protein deficiencies, mitochondrial dysfunction and oxidative stress. Primary sensory neurons (PSNs) in the dorsal root ganglia (DRGs) are the most vulnerable cells in FRDA, whose abnormal development and degeneration leads to the onset and early progression of ataxia. We generated PSNs from induced pluripotent stem cells (iPSCs) from FRDA patients and showed that they recapitulate the key pathogenic events in FRDA, including low FXN levels, loss of Fe-S proteins and impaired antioxidant responses. We also showed that FXN deficiency in these cells may be partially corrected by a pimelic benzamide histone deacetylase inhibitor, a class of potential therapeutics for FRDA. We generated and validated a cellular model of the most vulnerable neurons in FRDA, which can be used for further studies on pathogenesis and treatment approaches.

neuroscience↗