Giulia Gorrieri

Scopus Publications

Alternative splicing regulates PACC1 function and promotes acidosis-induced cytotoxicity
Serena Tamburro, Giulia Gorrieri, Niccolò Callegari, Floriana Guida, Francesca Antonini, Ilaria Musante, Simona Baldassari, Federico Zara, Paolo Scudieri
Frontiers in Cell and Developmental Biology, 2026
Introduction PACC1 (also named TMEM206 ) encodes a proton-activated chloride channel implicated in acid-induced cell death, but its tissue distribution, cellular expression, and isoform-specific roles are incompletely understood. Methods We mapped PACC1 expression and splicing across normal human tissues, with emphasis on the central nervous system, using RNAscope in situ hybridization, quantitative cell-type-specific co-detection, RT-PCR, and isoform-specific in situ probes. Functional properties of PACC1 splice variants were assessed by reconstituting each isoform in PACC1-deficient cells. Results PACC1 was broadly expressed across tissues, with especially high and uniform expression in the brain. Quantitative analyses revealed PACC1 localization in both neurons and astrocytes, with higher abundance in astrocytes. Two major splice variants, PACC1-V1 and PACC1-V2, were investigated, distinguished by exon 2 inclusion and exhibiting distinct tissue and developmental expression patterns. Functional assays indicated isoform-specific differences: PACC1-V2 predominantly localized to endosomes and prevented endosomal hyperacidification, whereas PACC1-V1 accumulated at the plasma membrane and enhanced acid-induced cell death. Conclusion Alternative splicing governs PACC1 channel trafficking and function. Isoform-specific behavior suggests distinct roles for PACC1 variants in cell development and responses to acid stress, particularly within the nervous system.
Modeling Mowat-Wilson syndrome with patient iPSCs reveals transcriptional and phenotypic defects in neural progenitors
Ilaria Musante, Giulia Gorrieri, Serena Tamburro, Giulia Ferrera, Simona Baldassari, Anna Fetta, Stefano Giuseppe Caraffi, Aglaia Vignoli, Giovanni Fiorito, Livia Garavelli, Maria Paola Canevini, Duccio Maria Cordelli, Federico Zara, Emilia Ricci, Paolo Scudieri
Neurobiology of Disease, 2026
Zinc finger E -box-binding homeobox 2 ( ZEB2 ) is a key transcription factor involved in multiple aspects of nervous system development, including neuronal specification, migration, and differentiation. Loss-of-function variants in ZEB2 cause Mowat-Wilson syndrome (MWS), a severe neurodevelopmental disorder characterized by intellectual disability, epilepsy, and brain structural abnormalities. In this study, we generated and characterized induced pluripotent stem cell (iPSC) lines from MWS patients carrying pathogenic ZEB2 variants. Patient-derived iPSCs retained full pluripotency and were capable of differentiating into all three germ layers, including neural lineages. Upon directed differentiation into neural progenitor cells (NPCs) and early neurons, we identified distinctive transcriptional alterations affecting neuroepithelial-to-radial glia transition and lineage specification. RNA-seq analysis revealed dysregulation of genes involved in cytoskeletal remodeling, extracellular matrix organization, and cell motility. Functional holographic live imaging confirmed a significant increase in motility behavior in MWS NPCs and early neurons, suggesting that altered cell dynamics may underlie aberrant neural circuit formation. Despite these changes, early neuronal markers such as MAP2 were expressed at comparable levels in MWS and control cells. Together, these findings uncover novel cellular and molecular phenotypes associated with ZEB2 deficiency and provide insight into how disrupted progenitor behavior and transcriptional mis-regulation may contribute to the neurodevelopmental features of MWS. • ZEB2 variants cause Mowat-Wilson syndrome (MWS) with severe neural abnormalities. • MWS iPSCs retain pluripotency but show altered neural differentiation. • MWS neural progenitors fail to repress non-neural genes, activating ECM and vascular pathways. • Patient-derived iPSCs provide a human model for studying MWS pathogenesis.
Generation of two iPSC lines from Mowat-Wilson syndrome patients carrying heterozygous ZEB2 mutations
Giulia Gorrieri, Serena Tamburro, Simona Baldassari, Sara Guerrisi, Federico Zara, Emilia Ricci, Duccio Maria Cordelli, Paolo Scudieri, Ilaria Musante
Stem Cell Research, 2024
ZEB2 is a protein-coding gene belonging to a very restricted family of transcription factors. ZEB2 acts mainly as a transcription repressor, is expressed in various tissues and its role is fundamental for the correct development of the nervous system. The best-known clinical picture associated with ZEB2 mutations is Mowat-Wilson syndrome, caused mostly by haploinsufficiency and characterized by possible multi-organ malformations, dysmorphic features, intellectual disability, and epilepsy. In this study we report the generation of IGGi004-A and IGGi005-A, iPSC clones from two patients carrying different heterozygous mutations in ZEB2, which can be used for disease modelling, pathophysiological studies and therapeutics testing.
ATP12A Proton Pump as an Emerging Therapeutic Target in Cystic Fibrosis and Other Respiratory Diseases
Michał Dębczyński, Giulia Gorrieri, Damian Mojsak, Floriana Guida, Federico Zara, Paolo Scudieri
Biomolecules, 2023
ATP12A encodes the catalytic subunit of the non-gastric proton pump, which is expressed in many epithelial tissues and mediates the secretion of protons in exchange for potassium ions. In the airways, ATP12A-dependent proton secretion contributes to complex mechanisms regulating the composition and properties of the fluid and mucus lining the respiratory epithelia, which are essential to maintain the airway host defense and the respiratory health. Increased expression and activity of ATP12A in combination with the loss of other balancing activities, such as the bicarbonate secretion mediated by CFTR, leads to excessive acidification of the airway surface liquid and mucus dysfunction, processes that play relevant roles in the pathogenesis of cystic fibrosis and other chronic inflammatory respiratory disorders. In this review, we summarize the findings dealing with ATP12A expression, function, and modulation in the airways, which led to the consideration of ATP12A as a potential therapeutic target for the treatment of cystic fibrosis and other airway diseases; we also highlight the current advances and gaps regarding the development of therapeutic strategies aimed at ATP12A inhibition.
Generation of an induced pluripotent stem cell line (IGGi002A) from nasal cells of a cystic fibrosis patient homozygous for the G542X-CFTR mutation
Michał Dębczyński, Damian Mojsak, Serena Tamburro, Simona Baldassari, Ilaria Musante, Rosaria Casciaro, Fabiana Ciciriello, Federico Zara, Paolo Scudieri, Giulia Gorrieri
Stem Cell Research, 2023
Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is a chloride channel defective in cystic fibrosis (CF). Several CFTR mutations are causative of CF, among which G542X is a nonsense mutation introducing a premature stop codon which prevents CFTR protein synthesis. We generated a new iPSC line from nasal cells carrying G542X homozygous mutation for CFTR: IGGi002A. This cell line has normal female karyotype, express pluripotency markers and could differentiate into three germ layers in vitro. This iPSC line may be used for disease modeling (cell differentiation and organoid formation) and development of personalized treatments by genome editing or pharmacological screening.
SLC26A9 as a Potential Modifier and Therapeutic Target in Cystic Fibrosis Lung Disease
Giulia Gorrieri, Federico Zara, Paolo Scudieri
Biomolecules, 2022
SLC26A9 belongs to the solute carrier family 26 (SLC26), which comprises membrane proteins involved in ion transport mechanisms. On the basis of different preliminary findings, including the phenotype of SlC26A9-deficient mice and its possible role as a gene modifier of the human phenotype and treatment response, SLC26A9 has emerged as one of the most interesting alternative targets for the treatment of cystic fibrosis (CF). However, despite relevant clues, some open issues and controversies remain. The lack of specific pharmacological modulators, the elusive expression reported in the airways, and its complex relationships with CFTR and the CF phenotype prevent us from conclusively understanding the contribution of SLC26A9 in human lung physiology and its real potential as a therapeutic target in CF. In this review, we summarized the various studies dealing with SLC26A9 expression, molecular structure, and function as an anion channel or transporter; its interaction and functional relationships with CFTR; and its role as a gene modifier and tried to reconcile them in order to highlight the current understanding and the gap in knowledge regarding the contribution of SLC26A9 to human lung physiology and CF disease and treatment.
Goblet Cell Hyperplasia Requires High Bicarbonate Transport to Support Mucin Release
Giulia Gorrieri, Paolo Scudieri, Emanuela Caci, Marco Schiavon, Valeria Tomati, Francesco Sirci, Francesco Napolitano, Diego Carrella, Ambra Gianotti, Ilaria Musante, Maria Favia, Valeria Casavola, Lorenzo Guerra, Federico Rea, Roberto Ravazzolo, Diego Di Bernardo, Luis J. V. Galietta
Scientific Reports, 2016
Goblet cell hyperplasia, a feature of asthma and other respiratory diseases, is driven by the Th-2 cytokines IL-4 and IL-13. In human bronchial epithelial cells, we find that IL-4 induces the expression of many genes coding for ion channels and transporters, including TMEM16A, SLC26A4, SLC12A2, and ATP12A. At the functional level, we find that IL-4 enhances calcium- and cAMP-activated chloride/bicarbonate secretion, resulting in high bicarbonate concentration and alkaline pH in the fluid covering the apical surface of epithelia. Importantly, mucin release, elicited by purinergic stimulation, requires the presence of bicarbonate in the basolateral solution and is defective in cells derived from cystic fibrosis patients. In conclusion, our results suggest that Th-2 cytokines induce a profound change in expression and function in multiple ion channels and transporters that results in enhanced bicarbonate transport ability. This change is required as an important mechanism to favor release and clearance of mucus.
Evaluation of a systems biology approach to identify pharmacological correctors of the mutant CFTR chloride channel
Emanuela Pesce, Giulia Gorrieri, Francesco Sirci, Francesco Napolitano, Diego Carrella, Emanuela Caci, Valeria Tomati, Olga Zegarra-Moran, Diego di Bernardo, Luis J.V. Galietta
Journal of Cystic Fibrosis, 2016