CURRICULUM
After my bachelor degree in Biology, I have started to work at the Neurological Institute Carlo Besta, in the Biochemistry and Genetic Unit at the beginning and, later, in the Neuromuscular Diseases and Neuroimmunology Unit, where I completed my education with a master degree. During my career in the laboratory, I have gained experience with animal models, in particular with zebrafish (Danio Rerio), that I am studying since 2012. Moreover, I increased my competence in cloning techniques, immunochemistry, biochemistry and histology procedures. While working for the Muscle Cell Biology Lab, I successfully applied my research skills on Neuromuscular Diseases study, supporting the research and the group. Furthermore, I had the possibility to write research projects and to find private funds to carry my own experiments. Recently, I have been involved in the study of muscle glycogen storage disorders, as Pompe Disease or Glycogenosis type II, with a particular attention to the autophagic process.
RESEARCH PROJECT
Characterization of Pompe Disease in vitro and in vivo models to test the efficacy of a new possible therapeutic molecule
Track: Experimental Neuroscience
Tutor: Dr. Mantegazza Renato
Excess glucose is stored as glycogen in skeletal muscle and liver as an energy substrate readily available through the glycolytic pathway. Perturbation of glycolytic enzymes results in glycogen storage disorders such as Pompe disease (PD) or glycogenosis type II. PD is an autosomal recessive metabolic disease with an estimated incidence of 1:40000 live births. PD is due to a defect of the lysosomal enzyme acid α-glucosidase (GAA), or acid maltase, necessary for glycogen degradation. The spectrum of disease severity encompasses a broad continuum of clinical phenotypes ranging from the most severe “classic” form, characterized by early childhood onset, severe cardiomyopathy, rapidly progressive course and fatal outcome before two years of age, to an “intermediate” infantile form expressing a milder phenotype, and to juvenile and adult forms characterized by prevalent involvement of skeletal muscle. Total deficiency of the GAA enzyme results in the severe infantile form, while partial deficiency is responsible for the intermediate and mild forms. Enzyme replacement therapy (ERT), where GAA is provided via intravenous infusion is the only therapy available since 2006. While ERT represented a major milestone in the treatment of patients with Pompe disease and it has been shown to be efficacious in infantile severe PD, not all late onset cases respond equally well to this treatment. Therefore, the correction of the skeletal muscle phenotype in late onset cases is still challenging, revealing a need for more effective therapies. GAA difficulties in restoring muscle function have been ascribed to a concomitant altered autophagy, a key molecular mechanism that maintains cellular homeostasis and ensures correct macromolecule turnover in the cell. However, it remains unclear how autophagy is disrupted in PD, since it is yet unknown if an excessive acceleration or reduction of this process is present. Notably, this recent defective autophagy finding in PD has stimulated both a reassessment of the pathogenic mechanisms as well as the investigation of new therapeutic approaches, including search for adjunctive and alternative therapies addressing both glycogen accumulation and autophagy. Among the small molecules to be explored for interfering with glycogen accumulation we have selected the Acid-3-Bromopyruvic (3-BrPA), an inhibitor of hexokinase (HK), which is a key glycolytic enzyme. In vitro and in vivo studies have reported this molecule to be an efficacious anti- tumor drug, in those tumor phenotypes in which cancer cells preferentially depend on glycolysis to produce adenosine triphosphate (ATP) for growth and proliferation. The anti- cancer property of this particular compound is due to its ability to inhibit glycolysis, by abolishing cell ATP production and consequently impeding the transformation by hexokinase of glucose into glucose-6- phosphate, and to trigger modulation of the autophagic process. Among the different hexokinase isoforms HKI, HKII, HKIII, and HKIV found in mammals, HKII is expressed at relatively high level only in skeletal muscle, adipose tissue, and heart. We propose to use this molecule, as inhibitor of the key glycolytic enzyme hexokinase-II, to modulate glycogen incorporation into cells. We will use zebrafish as in vivo model, in order to evaluate the effect of this specific molecule on the muscular system at subcellular detail. The demonstration of its role as HKII inhibitor and as autophagy modulator, will create the basis for developing a new strategy to improve muscle function in PD patients.
ABROAD EXPERIENCES
Oct 2009 -March 2010: Research Fellowship, The Hospital for Sick Children, Toronto, Canada, in the Program of Genetics and Genome Biology.
AWARDS
Prize for the best poster titled “Zebrafish as a Model to Investigate Dynamin 2-Related Diseases”. XV National Congress AIM – 18-23 May 2015
RECENT PUBLICATIONS AND CONGRESSES
Publications
- Bragato C, Carra S, Blasevich F, Salerno F, Brix A, Bassi A, Beltrame M, Cotelli F, Maggi L, Mantegazza R, Mora M. Glycogen storage in a zebrafish Pompe disease model is reduced by 3-BrPA treatment. Biochim Biophys Acta Mol Basis Dis. 2020
- Tavian D, Maggi, Mora M, Morandi L, Bragato C, Missaglia S. A novel PNPLA2 mutation causing total loss of RNA and protein expression in two NLSDM siblings with early-onset but slowly progressive severe myopathy. Genes & Disease. 2019
- Ferrari L*, Bragato C*, Brioschi L*, Spreafico M, Esposito S, Pezzotta A, Pizzetti F, Moreno- Fortuny A, Bellipanni G, Giordano A, Riva P, Frabetti F, Viani P, Cossu G, Mora M, Marozzi A, Pistocchi A. Pubblicazioni HDAC8 regulates canonical Wnt pathway to promote differentiation in skeletal muscles. J Cell Physiol. 2019
- Bottai D, Spreafico M, Pistocchi A, Fazio G, Adami R, Grazioli P, Canu A, Bragato C, Rigamonti S, Parodi C, Cazzaniga G, Biondi A, Cotelli F, Selicorni A, Massa V. Modeling
- Cornelia de Lange syndrome in vitro and in vivo reveals a role for cohesin complex in neuronal survival and differentiation. Hum Mol Genet. 2019
- Zanotti S, Gibertini S, Blasevich F, Bragato C, Ruggieri A, Saredi S, Fabbri M, Bernasconi P, Maggi L, Mantegazza R, Mora M. Exosomes and exosomal miRNAs from muscle-derived fibroblasts promote skeletal muscle fibrosis. Matrix Biol. 2018
- Cocola C, Molgora S, Piscitelli E, Veronesi MC, Greco M, Bragato C, Moro M, Crosti M, Gray B, Milanesi L, Grieco V, Luvoni GC, Kehler J, Bellipanni G, Reinbold R, Zucchi I, Giordano A. FGF2 and EGF Are Required for Self-Renewal and Organoid Formation of Canine Normal and Tumor Breast Stem Cells. J Cell Biochem. 2017
- Bragato C, Gaudenzi G, Blasevich F, Pavesi G, Maggi L, Giunta M, Cotelli F, Mora M. Zebrafish as a Model to Investigate Dynamin 2-Related Diseases. Sci Rep. 2016
- Ardissone A, Bragato C, Blasevich F, Maccagnano E, Salerno F, Gandioli C, Morandi L, Mora M, Moroni I. SEPN1-related myopathy in three patients: novel mutations and diagnostic clues. Eur J Pediatr. 2016
- Zanotti S, Bragato C, Zucchella A, Maggi L, Mantegazza R, Morandi L, Mora M. Anti-fibrotic effect of pirfenidone in muscle derived-fibroblasts from Duchenne muscular dystrophy patients. Life Sci. 2016
- Fattori F, Maggi L, Bruno C, Cassandrini D, Codemo V, Catteruccia M, Tasca G, Berardinelli A, Magri F, Pane M, Rubegni A, Santoro L, Ruggiero L, Fiorini P, Pini A, Mongini T, Messina S, Brisca G, Colombo I, Astrea G, Fiorillo C, Bragato C, Moroni I, Pegoraro E, D’Apice MR, Alfei E, Mora M, Morandi L, Donati A, Evilä A, Vihola A, Udd B, Bernansconi P, Mercuri E, Santorelli FM, Bertini E, D’Amico A. Centronuclear myopathies: genotype-phenotype correlation and frequency of defined genetic forms in an Italian cohort. J Neurol. 2015
*=equal contribution
Congresses
- (poster) A new therapeutic strategy for glycogen storage disorders. C Bragato, S Saredi, F Blasevich, M Beltrame, M Mora, R Mantegazza. Zebrafish disease models conference (ZDM11), 10-13 July 2018 – Leiden (Netherlands)
- (poster) Identification and characterization of two dynamin-2 isoforms in the zebrafish: new insights into centronuclear myopathies. C. Bragato, G. Gaudenzi, M. Giunta, G. Pavesi, S. Gibertini, F. Salerno, F. Cotelli, M. Mora, XIII National Congress AIM – 16-18 May 2013 – Stresa (Vb)
- (poster) Biological, histopathological and clinical features in muscle biopsies of Pompe Disease patients C Bragato, R Violano, S Saredi, M Ripolone, F Salerno, B Pasanisi, L. Maggi, L. Morandi, M Moggio, M Mora, XIII National Congress AIM – 16-18 May 2013 – Stresa (Vb).
- (poster) Expression in zebrafish of mutated human DNM2 produces defects similar to those in human centronuclear myopathy and Charcot-Marie-Tooth neuropathy. Bragato C,
- Gaudenzi G, Blasevich F, Pavesi G, Maggi L, Giunta M, Cotelli F, Mora M. XV National Congress AIM – 18-23 May 2015.
- (poster) A translational approach to neuromuscular diseases based on zebrafish studies: from human to zebrafish and back. Bragato C, Blasevich F, Carra S, Bassi A, Cotelli F, Beltrame M, Mora M. 1st Italian Zebrafish Meeting (ZFIM), 2-3 February 2017.
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