Alessandra d'Azzo, Ph.D.
Genetics / Tumor Cell Biology
St. Jude Children's Research Hospital
Department of Anatomy and Neurobiology
St. Jude Children's Research Hospital
Department of Genetics
Memphis, TN 38105
Email: Alessandra d'Azzo
- Ph.D. Institution: University of Milano, Milan Italy; Erasmus University, Rotterdam, The Netherlands
The primary scope of this research program is to elucidate the fundamental role of the lysosomal system in normal cellular metabolism and in pathological conditions associated with lysosomal storage disorders (LSD).
Using a combination of molecular, genetic, and biochemical approaches, they have identified a multiprotein complex of three lysosomal hydrolases: protective protein/cathepsin A (PPCA), -galactosidase (-Gal), and neuraminidase (Neur). In the complex, PPCA (a serine carboxypeptidase) directly associates with the two glycosidases, a configuration needed for their intracellular routing, lysosomal activity, and stability. Three genetically distinct, human neurodegenerative LSD are caused by either single or combined deficiency of these enzymes: galactosialidosis, GM1-gangliosidosis, and sialidosis. To date, there is no effective therapy for these diseases. Using both in vitro systems and laboratory animals, they investigate the cell-specific expression and regulation of these enzymes, their intracellular trafficking, mode/site of association and activation, and their interaction with the substrates they cleave. They are also developing new therapeutic strategies in animal models for the future treatment of patients with these LSD. Greater knowledge of the function of these and other lysosomal proteins in the normal lysosome, as well as a better understanding of the structural and biochemical basis of the diseases, will aid in the design of new drugs and therapies.
The experimental approaches include: generation and characterization of knockout and transgenic mice; correction of affected mice by transplantation with transgenic over expressing or retrovirally transduced bone marrow; expression and regulation of normal and mutant enzymes in prokaryotic/eukaryotic cell systems; and crystal structure determination of over expressed proteins.
- Bonardi D, Ravasio V, Borsani G, d'Azzo A, Bresciani R, Monti E, Giacopuzzi E. In silico identification of new putative pathogenic variants in the neu1 sialidase gene affecting enzyme function and subcellular localization. PLoS One. 2014 Aug 25;9(8):e104229. doi: 10.1371/journal.pone.0104229. eCollection 2014. PubMed PMID: 25153125; PubMed Central PMCID: PMC4143216.
- Bonten EJ, Annunziata I, d'Azzo A. Lysosomal multienzyme complex: pros and cons of working together. Cell Mol Life Sci. 2014 Jun;71(11):2017-32. doi: 10.1007/s00018-013-1538-3. Epub 2013 Dec 15. Review. PubMed PMID: 24337808; PubMed Central PMCID: PMC4037752.
- Annunziata I, Patterson A, Helton D, Hu H, Moshiach S, Gomero E, Nixon R, d'Azzo A. Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-Î² secretion via deregulated lysosomal exocytosis. Nat Commun. 2013;4:2734. doi: 10.1038/ncomms3734. PubMed PMID: 24225533; PubMed Central PMCID: PMC4015463.
- Caciotti A, Catarzi S, Tonin R, Lugli L, Perez CR, Michelakakis H, Mavridou I, Donati MA, Guerrini R, d'Azzo A, Morrone A. Galactosialidosis: review and analysis of CTSA gene mutations. Orphanet J Rare Dis. 2013 Aug 2;8:114. doi: 10.1186/1750-1172-8-114. Review. PubMed PMID: 23915561; PubMed Central PMCID: PMC3737020.
- Bonten EJ, Yogalingam G, Hu H, Gomero E, van de Vlekkert D, d'Azzo A. Chaperone-mediated gene therapy with recombinant AAV-PPCA in a new mouse model of type I sialidosis. Biochim Biophys Acta. 2013 Oct;1832(10):1784-92. doi: 10.1016/j.bbadis.2013.06.002. Epub 2013 Jun 12. PubMed PMID: 23770387; PubMed Central PMCID: PMC3794473.
- Romancino DP, Paterniti G, Campos Y, De Luca A, Di Felice V, d'Azzo A, Bongiovanni A. Identification and characterization of the nano-sized vesicles released by muscle cells. FEBS Lett. 2013 May 2;587(9):1379-84. doi: 10.1016/j.febslet.2013.03.012. Epub 2013 Mar 20. PubMed PMID: 23523921.