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.
- 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.
- Annunziata I, Patterson A, d'Azzo A. Mitochondria-associated ER membranes (MAMs) and glycosphingolipid enriched microdomains (GEMs): isolation from mouse brain. J Vis Exp. 2013 Mar 4;(73):e50215. doi: 10.3791/50215. PubMed PMID: 23486347.
- Romancino DP, Anello L, Morici G, d'Azzo A, Bongiovanni A, Di Bernardo M. Identification and characterization of PlAlix, the Alix homologue from the Mediterranean sea urchin Paracentrotus lividus. Dev Growth Differ. 2013 Feb;55(2):237-46. doi: 10.1111/dgd.12023. Epub 2013 Jan 10. PubMed PMID: 23302023.
- Lehman A, Mattman A, Sin D, Pare P, Zong Z, d'Azzo A, Campos Y, Sirrs S, Hinek A. Emphysema in an adult with galactosialidosis linked to a defect in primary elastic fiber assembly. Mol Genet Metab. 2012 May;106(1):99-103. doi: 10.1016/j.ymgme.2012.02.004. Epub 2012 Feb 8. PubMed PMID: 22386972.
- Bongiovanni A, Romancino DP, Campos Y, Paterniti G, Qiu X, Moshiach S, Di Felice V, Vergani N, Ustek D, d'Azzo A. Alix protein is substrate of Ozz-E3 ligase and modulates actin remodeling in skeletal muscle. J Biol Chem. 2012 Apr 6;287(15):12159-71. doi: 10.1074/jbc.M111.297036. Epub 2012 Feb 13. PubMed PMID: 22334701; PubMed Central PMCID: PMC3320967.
- Hu H, Gomero E, Bonten E, Gray JT, Allay J, Wu Y, Wu J, Calabrese C, Nienhuis A, d'Azzo A. Preclinical dose-finding study with a liver-tropic, recombinant AAV-2/8 vector in the mouse model of galactosialidosis. Mol Ther. 2012 Feb;20(2):267-74. doi: 10.1038/mt.2011.227. Epub 2011 Oct 18. PubMed PMID: 22008912; PubMed Central PMCID: PMC3277225.