Alessandra d'Azzo, PhD

Education

• PhD Institution: University of Milano, Milan Italy; Erasmus University, Rotterdam, The Netherlands

Links

• St Jude Faculty - Alessandra d'Azzo

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.

Representative Publications

• Lawrence R, Van Vleet JL, Mangini L, Harris A, Martin N, Clark W, Chandriani S, LeBowitz JH, Giugliani R, d'Azzo A, Yogalingam G, Crawford BE. Characterization of glycan substrates accumulating in GM1 Gangliosidosis. Mol Genet Metab Rep. 2019 Nov 3;21:100524. doi: 10.1016/j.ymgmr.2019.100524. eCollection 2019 Dec. PubMed PMID: 31720227; PubMed Central PMCID: PMC6838976.
• Caciotti A, Melani F, Tonin R, Cellai L, Catarzi S, Procopio E, Chilleri C, Mavridou I, Michelakakis H, Fioravanti A, d'Azzo A, Guerrini R, Morrone A. Type I sialidosis, a normosomatic lysosomal disease, in the differential diagnosis of late-onset ataxia and myoclonus: An overview. Mol Genet Metab. 2019 Oct 31. pii: S1096-7192(19)30537-2. doi: 10.1016/j.ymgme.2019.09.005. [Epub ahead of print] Review. PubMed PMID: 31711734.
• Chen JC, Luu AR, Wise N, Angelis R, Agrawal V, Mangini L, Vincelette J, Handyside B, Sterling HJ, Lo MJ, Wong H, Galicia N, Pacheco G, Van Vleet J, Giaramita A, Fong S, Roy SM, Hague C, Lawrence R, Bullens S, Christianson TM, d'Azzo A, Crawford BE, Bunting S, Lebowitz JH, Yogalingam G. Intracerebroventricular enzyme replacement therapy with Beta-Galactosidase reverses brain pathologies due to GM1 gangliosidosis in mice. J Biol Chem. 2019 Sep 3. pii: jbc.RA119.009811. doi: 10.1074/jbc.RA119.009811. [Epub ahead of print] PubMed PMID: 31481471.
• Annunziata I, van de Vlekkert D, Wolf E, Finkelstein D, Neale G, Machado E, Mosca R, Campos Y, Tillman H, Roussel MF, Andrew Weesner J, Ellen Fremuth L, Qiu X, Han MJ, Grosveld GC, d'Azzo A. MYC competes with MiT/TFE in regulating lysosomal biogenesis and autophagy through an epigenetic rheostat. Nat Commun. 2019 Aug 9;10(1):3623. doi: 10.1038/s41467-019-11568-0. PubMed PMID: 31399583; PubMed Central PMCID: PMC6689058.
• van de Vlekkert D, Demmers J, Nguyen XX, Campos Y, Machado E, Annunziata I, Hu H, Gomero E, Qiu X, Bongiovanni A, Feghali-Bostwick CA, d'Azzo A. Excessive exosome release is the pathogenic pathway linking a lysosomal deficiency to generalized fibrosis. Sci Adv. 2019 Jul 17;5(7):eaav3270. doi: 10.1126/sciadv.aav3270. eCollection 2019 Jul. PubMed PMID: 31328155; PubMed Central PMCID: PMC6636989.
• Platt FM, d'Azzo A, Davidson BL, Neufeld EF, Tifft CJ. Publisher Correction: Lysosomal storage diseases. Nat Rev Dis Primers. 2019 May 17;5(1):34. doi: 10.1038/s41572-019-0089-9. PubMed PMID: 31101820.

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