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.
- Regier DS, Proia RL, D'Azzo A, Tifft CJ. The GM1 and GM2 Gangliosidoses: Natural History and Progress toward Therapy. Pediatr Endocrinol Rev. 2016 Jun;13 Suppl 1:663-73. PubMed PMID: 27491214.
- Campos Y, Qiu X, Gomero E, Wakefield R, Horner L, Brutkowski W, Han YG, Solecki D, Frase S, Bongiovanni A, d'Azzo A. Alix-mediated assembly of the actomyosin-tight junction polarity complex preserves epithelial polarity and epithelial barrier. Nat Commun. 2016 Jun 23;7:11876. doi: 10.1038/ncomms11876. PubMed PMID: 27336173; PubMed Central PMCID: PMC4931029.
- Machado E, White-Gilbertson S, van de Vlekkert D, Janke L, Moshiach S, Campos Y, Finkelstein D, Gomero E, Mosca R, Qiu X, Morton CL, Annunziata I, d'Azzo A. Regulated lysosomal exocytosis mediates cancer progression. Sci Adv. 2015 Dec 18;1(11):e1500603. doi: 10.1126/sciadv.1500603. eCollection 2015 Dec. PubMed PMID: 26824057; PubMed Central PMCID: PMC4730843.
- Katorcha E, Klimova N, Makarava N, Savtchenko R, Pan X, Annunziata I, Takahashi K, Miyagi T, Pshezhetsky AV, d'Azzo A, Baskakov IV. Loss of Cellular Sialidases Does Not Affect the Sialylation Status of the Prion Protein but Increases the Amounts of Its Proteolytic Fragment C1. PLoS One. 2015 Nov 16;10(11):e0143218. doi: 10.1371/journal.pone.0143218. eCollection 2015. PubMed PMID: 26569607; PubMed Central PMCID: PMC4646690.
- Neves Jde C, Rizzato VR, Fappi A, Garcia MM, Chadi G, van de Vlekkert D, d'Azzo A, Zanoteli E. Neuraminidase-1 mediates skeletal muscle regeneration. Biochim Biophys Acta. 2015 Sep;1852(9):1755-64. doi: 10.1016/j.bbadis.2015.05.006. Epub 2015 May 19. PubMed PMID: 26001931.
- Akgoc Z, Sena-Esteves M, Martin DR, Han X, d'Azzo A, Seyfried TN. Bis(monoacylglycero)phosphate: a secondary storage lipid in the gangliosidoses. J Lipid Res. 2015 May;56(5):1006-13. doi: 10.1194/jlr.M057851. Epub 2015 Mar 20. PubMed PMID: 25795792; PubMed Central PMCID: PMC4409277.