ALESSANDRA D'AZZO, Ph.D.

Member

Genetics / Tumor Cell Biology

St. Jude Children's Research Hospital

Affiliated Professor

Department of Anatomy and Neurobiology

The University of Tennessee Health Science Center

Address

St. Jude Children's Research Hospital

Department of Genetics

Memphis, TN 38105

Education

Ph.D. Institution: University of Milano, Milan Italy; Erasmus University, Rotterdam, The Netherlands

Research Interests

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.

Links

St Jude Faculty - Alessandra d'Azzo

Recent Publications

• Sano R, Annunziata I, Patterson A, Moshiach S, Gomero E, Opferman J, Forte M, d'Azzo A. GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca(2+)-dependent mitochondrial apoptosis. Mol Cell. 2009 Nov 13;36(3):500-11. PMID: 19917257
• Wu X, Steigelman KA, Bonten E, Hu H, He W, Ren T, Zuo J, d'Azzo A. Vacuolization and alterations of lysosomal membrane proteins in cochlear marginal cells contribute to hearing loss in neuraminidase 1-deficient mice. Biochim Biophys Acta. 2009 Oct 24; [Epub ahead of print] PMID: 19857571
• Wang D, Zaitsev S, Taylor G, d'Azzo A, Bonten E. Protective protein/cathepsin A rescues N-glycosylation defects in neuraminidase-1. Biochim Biophys Acta. 2009 Apr;1790(4):275-82. PMID: 19714866
• Bonten EJ, Campos Y, Zaitsev V, Nourse A, Waddell B, Lewis W, Taylor G, d'Azzo A. Heterodimerization of the sialidase NEU1 with the chaperone protective protein/cathepsin A prevents its premature oligomerization. J Biol Chem. 2009 Oct 9;284(41):28430-41. Epub 2009 Aug 7. PMID: 19666471
• Caciotti A, Di Rocco M, Filocamo M, Grossi S, Traverso F, d'Azzo A, Cavicchi C, Messeri A, Guerrini R, Zammarchi E, Donati MA, Morrone A. Type II sialidosis: review of the clinical spectrum and identification of a new splicing defect with chitotriosidase assessment in two patients. J Neurol. 2009 Nov;256(11):1911-5. Epub 2009 Jul 1. PMID: 19568825
• Wang D, Zaitsev S, Taylor G, d'Azzo A, Bonten E. Protective Protein/Cathepsin A Rescues N-glycosylation defects in Neuraminidase-1. Biochim Biophys Acta. 2009 Jan 26; [Epub ahead of print] PMID: 19364485

view complete list of references (pubmed link)