Dissecting molecular mechanisms of inborn errors of metabolism
Margherita Ruoppolo holds a degree in Chemistry and a Ph.D. in Chemistry from the University of Naples “Federico II.”
From 1993 to 1994, she conducted research at the Biology Laboratory of the University of Kent in Canterbury, UK, focusing on the folding process of disulfide-containing proteins, both in vitro and in vivo.
She began her academic career in 1996 as a Researcher in Biochemistry (BIO/10) at the University of Salerno. In 2001, she was appointed Associate Professor in the Faculty of Medicine and Surgery at the University of Naples “Federico II,” where she has served as a Full Professor of Biochemistry since 2007.
Since 2003, she has been leading the Interdepartmental Program for the development of innovative spectroscopic technologies for screening and diagnosis of diseases at the Department of Laboratory Medicine, University Hospital “Federico II.”
Her scientific work is mainly focused on newborn screening for inherited metabolic disorders, an area in which she has extensive experience. Since 2017, she has been the Head of the Newborn Screening Laboratory of the Campania Region, where she oversees the validation of new biomarkers and the optimization of diagnostic cut-off values. Her research aims to enhance the sensitivity and specificity of screening programs through the integration of multi-omics data.
She has contributed to several national and international projects focused on the harmonization of diagnostic protocols and has authored numerous peer-reviewed publications in the fields of metabolomics and inherited metabolic diseases. Her research also involves the development of differential and functional proteomics methodologies in molecular medicine. She analyzes and interprets mass spectrometry (MS) data using tools such as MaxQuant, Proteome Discoverer, and Skyline, and performs bioinformatics analyses with GO classification, Perseus, and Ingenuity Pathway Analysis.
She is actively involved in the training of master and PhD students and residents, with a strong commitment to promoting good laboratory practices in clinical settings.
Her work bridges the gap between basic research and clinical application. She collaborates with several research groups on studies related to isolated and combined methylmalonic acidemia and glycogen storage diseases. Her team developed several cellular models of disease by genetic engineering. Cellular sistems are used to study the cell signaling mediating metabolic alteration. Her team have access to several animal models through a dense network of collaboration.
Inborn errors of metabolism (IEM) are genetic disorders that are caused by alterations of a specific enzymatic reaction. IEM can be pleiotropic, and can involve virtually any organ or system. Initial clinical presentation can occur any time from prenatal development through adulthood, and specific environmental triggers are crucial to determine an individual patient phenotype. The genetic basis of IEMs is extremely heterogeneous and can involve any type of genetic defects. The diagnose of IEM depends on the specific disorder or presenting phenotype. Recently, tandem mass spectrometry has facilitated the rapid and economical evaluation of a broad spectrum of metabolites, enabling the timely diagnosis of many disorders, thereby facilitating early institution of therapy by national newborn screening programme.
This project aims to use a combination of state-of-the-art “omics” methodologies to comprehensively screen for protein and metabolite landmarks that can unveil pathophysiological mechanisms in a classes of IEM named organic acidemias (OA) (4-6), caused by mutations in genes encoding enzymes involved in amino acid catabolism. The OA are biochemically characterized by tissue accumulation of non-amino organic acids and their CoA, L-carnitine and glycine esters upstream of the enzymatic blockage. Neurological signs are prominent in OA, implying a high vulnerability of the Central nervous System (CNS), which was shown to be age-dependent and region-specific. Treatment generally reduces toxic levels of metabolites in blood, but remains insufficient to prevent many of the long-term neurological and systemic complications. Therapy does not halt progressive multi-organ dysfunction, leading to severe disability and even death. Thus, it is mandatory to elucidate the molecular bases of organic acidemias to improve the diagnostic strategies and the treatment follow-up and to unveil altered pathways that could be targeted for therapeutic purposes. This project aims:
(i) to define the OMIC pathological signature of OAs in order to characterize the unknown patho-mechanism, linked to disease progression
(ii) to identify altered metabolic pathways in order to improve diagnostic strategies, implement therapeutic protocols and optimize follow-up in order to prevent negative prognosis.
(iii) to develop innovative therapeutic strategies through the use of nanomedicine, such as the use of nanovectors in order to: a) improve the delivery of therapeutic agents already in clinical use or still experimental and b) evaluate new drugs directed against new molecular targets identified in the present study.
Hereditary metabolic diseases (IME) are rare genetic conditions caused by alterations in specific enzymes, which are essential for the correct functioning of our metabolism. They can affect any organ or system of the body and appear at any time in life, even in the first few days after birth. Some environmental factors, such as diet or infections, can cause or worsen the symptoms.
Early diagnosis is essential to be able to intervene promptly with appropriate therapies. In this context, tandem mass spectrometry, a modern and highly sensitive analytical technique, has revolutionized neonatal screening, allowing many of these diseases to be identified early.
The research group led by Professor Margherita Ruoppolo has been working for years to improve the diagnosis and treatment of these diseases, focusing in particular on:
• organic acidemias, a group of diseases caused by defects in the metabolism of amino acids, and
• glycogenosis, linked to an alteration in the metabolism of glycogen, the body's main reserve of sugars.
These diseases can cause an accumulation of toxic substances in the blood and tissues, with serious effects especially on the central nervous system. Although current therapies help reduce the levels of these substances, they are not always able to prevent long-term damage.
For this reason, Professor Ruoppolo's research project has three main objectives:
1. Discover new "molecular signatures" of the disease, using innovative approaches called "omics", which analyze proteins and metabolites in an integrated way.
2. Identify the altered mechanisms underlying the progression of the disease, to improve the diagnosis and monitoring of patients over time.
This research, deeply oriented towards clinical translation, aims to improve the quality of life of people affected by rare metabolic diseases, offering them more precise diagnoses and increasingly personalized therapies.
- Sabrina Bianco, assegnista di ricerca
- Marianna Caterino, PA
- Dino Cevenini, PA
- Michele Costanzo, RtdA
- Marica Cozzolino, Dottoranda
Digital microfluidic platform for dried blood spot newborn screening of lysosomal storage diseases in Campania region (Italy): Findings from the first year pilot project-Melania Scarcella, Simona Fecarotta, Marianna Alagia, Ferdinando Barretta, Fabiana Uomo, Valeria De Pasquale, Hari S. Patel, Pietro Strisciuglio, Giancarlo Parenti, Giulia Frisso, Luigi Michele Pavone, Margherita Ruoppolo -Mol Genet Metab. 2024 Dec 31:109008. doi: 10.1016/j.ymgme.2024.109008.
Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions -Costanzo M, Cevenini A, Kollipara L, Caterino M, Bianco S, Pirozzi F, Scerra G, D'Agostino M, Pavone LM, Sickmann A, Ruoppolo M.-Cell Biosci. 2024 May 17;14(1):63. doi: 10.1186/s13578-024-01245-1. PMID: 38760822; PMCID: PMC11102240
Expanded Newborn Screening in Italy Using Tandem Mass Spectrometry: Two Years of National Experience - Ruoppolo, Margherita, Malvagia, Sabrina, Boenzi, Sara, Carducci, Carla, Dionisi-Vici, Carlo, Teofoli, Francesca, Burlina, Alberto, Angeloni, Antonio, Aronica,Tommaso, Bordugo, Andrea, Bucci, Ines, Camilot, Marta, Carbone, Maria Teresa, Cardinali, Roberta, Carducci, Claudia, Cassanello, Michela, Castana, Cinzia, Cazzorla, Chiara, Ciatti, Renzo, Ferrari, Simona, Frisso, Giulia, Funghini, Silvia, Furlan, Francesca, Gasperini, Serena, Gragnaniello, Vincenza, Guzzetti, Chiara, La Marca, Giancarlo, La Spina, Luisa, Lorè, Tania, Meli, Concetta, Messina, MariaAnna, Morrone, Amelia, Nardecchia, Francesca, Ortolano, Rita, Parenti, Giancarlo, Pavanello, Enza, Pieragostino, Damiana, Pillai, Sara, Porta, Francesco, Righetti, Francesca, Rossi, Claudia, Rovelli, Valentina, Salina, Alessandro, Santoro, Laura, Sauro, Pina, Schiaffino, Maria Cristina, Simonetti, Simonetta, Vincenzi, Monica, Tarsi, Elisabetta, Uccheddu, Anna Paola -(2022). INTERNATIONAL JOURNAL OF NEONATAL SCREENING, vol. 8,ISSN: 2409-515X, doi: 10.3390/ijns8030047
Galactosemia: Biochemistry, Molecular Genetics, Newborn Screening, and Treatment - Succoio Mariangela, Sacchettini Rosa, Rossi Alessandro, Parenti Giancarlo, Ruoppolo Margherita -(2022). BIOMOLECULES, vol. 12, ISSN: 2218-273X, doi: 10.3390/biom12070968.
Proteomics Reveals that Methylmalonyl-CoA Mutase Modulates Cell Architecture and Increases Susceptibility to Stress -Michele Costanzo, Marianna Caterino, Armando Cevenini, Vincent Jung, Cerina Chhuon, Joanna Lipecka, Roberta Fedele, Ida Chiara Guerrera and Margherita Ruoppolo - Int. J. Mol. Sci. 2020, July 21(14), 4998; doi:10.3390/ijms21144998.
Complete list of published work in PubMed
Bibliometric data (Scopus, May 2025)
- Number of publications: 132
- H index: 32
- Total number of citations: 3307