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Alessandra d'Azzo, PhD
Alessandra d'Azzo, PhD

Alessandra d'Azzo, PhD

Member, St. Jude Faculty

  • Jewelers For Children Endowed Chair in Genetics and Gene Therapy



MS – University of Pavia, Italy (1979)
PhD – University of Milano, Italy (1973)
PhD – Erasmus University, Rotterdam, The Netherlands (1982)

Research Interests

  • In animal models of pediatric lysosomal storage diseases, we study mechanisms of pathogenesis downstream of lysosomal enzymes that are also implicated in adult diseases and aging (i.e. Alzheimer’s Disease, fibrosis, and cancer).
  • In animal models of OZZ and its target substrates, we study the regulation of cytoskeletal-associated proteins, and membrane dynamics.

Lysosomal Biogenesis and Lysosomal Storage Diseases

Therapy for Lysosomal Storage Diseases

Regulation and function of OZZ-E3, a muscle-specific ubiquitin ligase complex

d'Azzo Lab Members

Selected Publications

Bongiovanni A, Cusimano A, Annunziata I, d'Azzo A. Sialylation of host proteins as targetable risk factor for COVID-19 susceptibility and spreading: A hypothesis. FASEB Bioadv Jan 13;3(3):192-197, 2021. doi: 10.1096/fba.2020-00073, 2021. PMID: 33733058

Machado ER, Annunziata I, van de Vlekkert D, Grosveld GC, d'Azzo A. Lysosomes and cancer progression: A malignant liaison. Front Cell Dev Biol Feb 26;9:642494, 2021. doi: 10.3389/fcell.2021.642494. PMID: 33718382

Van De Vlekkert D, Qiu X, Annunziata I, d'Azzo A. Isolation, purification and characterization of exosomes from fibroblast cultures of skeletal muscle. Bio Protoc Apr 5;10(7):e3576, 2020. doi: 10.21769/BioProtoc.3576. PMID: 33659546

Van De Vlekkert D, Machado E, d'Azzo A. Analysis of Generalized Fibrosis in Mouse Tissue Sections with Masson's Trichrome Staining. Bio Protoc May 20;10(10):e3629, 2020. doi: 10.21769/BioProtoc.3629. PMID: 33659302

Cadaoas J, Hu H, Boyle G, Gomero E, Mosca R, Jayashankar K, Machado M, Cullen S, Guzman B, van de Vlekkert D, Annunziata I, Vellard M, Kakkis E, Koppaka V, d'Azzo A. Galactosialidosis: preclinical enzyme replacement therapy in a mouse model of the disease, a proof of concept. Mol Ther Methods Clin Dev Nov 20;20:191-203. doi: 10.1016/j.omtm.2020.11.012. PMID: 33426146 

Daich Varela M, Zein WM, Toro C, Groden C, Johnston J, Huryn LA, d'Azzo A, Tifft CJ, FitzGibbon EJ. A sialidosis type I cohort and a quantitative approach to multimodal ophthalmic imaging of the macular cherry-red spot. Br J Ophthalmol Aug 4:bjophthalmol-2020-316826, 2020. doi: 10.1136/bjophthalmol-2020-316826. Online ahead of print. PMID: 32753397

Luu AR, Wong C, Agrawal V, Wise N, Handyside B, Lo MJ, Pacheco G, Felix JB, Giaramita A, d'Azzo A, Vincelette J, Bullens S, Bunting S, Christianson TM, Hague CM, LeBowitz JH, Yogalingam G. Intermittent enzyme replacement therapy with recombinant human β-galactosidase prevents neuraminidase 1 deficiency. J Biol Chem Sep 25;295(39):13556-13569, 2020. doi: 10.1074/jbc.RA119.010794. PMID: 32727849

Han MJ, Annunziata I, Weesner J, Campos Y, Salie M, O'Reilly C, d'Azzo A. Generation of human induced pluripotent stem cells (hIPSCs) from sialidosis types I and II patients with pathogenic neuraminidase 1 mutations. Stem Cell Res Jul;46:101836, 2020. doi: 10.1016/j.scr.2020.101836. PMID: 32485644

Van de Vlekkert D, Qiu X, Annunziata I, d'Azzo A. Isolation and Characterization of Exosomes from Skeletal Muscle Fibroblasts. J Vis Exp May 16;(159). doi: 10.3791/61127. PMID: 32478721

d'Azzo A, Annunziata I. Transcription factor competition regulates lysosomal biogenesis and autophagy. Mol Cell Oncol Jan 6;7(2):1685840, 2020. doi: 10.1080/23723556.2019.1685840. PMID: 32158913

Mosca R, van de Vlekkert D, Campos Y, Fremuth LE, Cadaoas J, Koppaka V, Kakkis E, Tifft C, Toro C, Allievi S, Gellera C, Canafoglia L, Visser G, Annunziata I, d'Azzo A. Conventional and Unconventional Therapeutic Strategies for Sialidosis Type I. J Clin Med Mar 4;9(3):695, 2020. doi: 10.3390/jcm9030695. PMID: 32143456 

Ohnota H, Nakazawa H, Hayashi M, Okuhara Y, Honda T, d'Azzo A, Sekijima Y. Skeletal muscle cells derived from mouse skin cultures. Biochem Biophys Res Commun  Jul 23;528(2):398-403, 2020. doi: 10.1016/j.bbrc.2019.12.067. PMID: 31926596

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 Feb;129(2):47-58, 2020. doi: 10.1016/j.ymgme.2019.09.005. PMID: 31711734

Chen JC, Luu AR, Wise N, Angelis R, Agrawal V, Mangini L, Vincelette J, Handyside B, Sterling H, 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 β-galactosidase reverses brain pathologies due to GM1 gangliosidosis in mice. J Biol Chem Sep 25;295(39):13532-13555, 2020. doi: 10.1074/jbc.RA119.009811. PMID: 31481471

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 Nov 3;21:100524, 2019. doi: 10.1016/j.ymgmr.2019.100524. PMID: 31720227

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 5(7):eaav3270, 2019. doi: 10.1126/sciadv.aav3270. PMID: 31328155.

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 10(1):3623, 2019. doi: 10.1038/s41467-019-11568-0. PMID: 31399583.

Platt FM, d'Azzo A, Davidson BL, Neufeld EF, Tifft CJ. Lysosomal storage diseases. Nat Rev Dis Primers 4(1):27, 2018. doi: 10.1038/s41572-018-0025-4. Review. PMID: 30275469.

Romancino DP, Buffa V, Caruso S, Ferrara I, Raccosta S, Notaro A, Campos Y, Noto R, Martorana V, Cupane A, Giallongo A, d'Azzo A, Manno M, Bongiovanni A. Palmitoylation is a post-translational modification of Alix regulating the membrane organization of exosome-like small extracellular vesicles. Biochim Biophys Acta Gen Subj 1862(12):2879-2887, 2018. doi: 10.1016/j.bbagen.2018.09.004. PMID: 30251702.

Annunziata I, Sano R, d'Azzo A. Mitochondria-associated ER membranes (MAMs) and lysosomal storage diseases. Cell Death Dis 9(3):328, 2018. doi: 10.1038/s41419-017-0025-4. Review. PMID: 29491402.

Annunziata I, d'Azzo A. Galactosialidosis: historic aspects and overview of investigated and emerging treatment options. Expert Opin Orphan Drugs 5(2):131-141, 2017. doi: 10.1080/21678707.2016.1266933. PMID: 28603679.

Regier DS, Proia RL, d'Azzo A, Tifft CJ. The GM1 and GM2 Gangliosidoses: Natural History and Progress toward Therapy. Pediatr Endocrinol Rev 13(suppl 1):663-73, 2016. 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 23(7):11876, 2016. doi: 10.1038/ncomms11876. PMID: 2733617.

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 1(11):e1500603, 2015. doi: 10.1126/sciadv.1500603. PMID: 26824057.

Neves JC, 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 1852(9):1755-64, 2015.

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 56(5):1006-13, 2015.

Heinecke KA, Luoma A, D'azzo A, Kirschner DA, Seyfried TN. Myelin abnormalities in the optic and sciatic nerves in mice with GM1-gangliosidosis. ASN Neuro 2015 7(1), 2015. doi: 10.1177/1759091415568913. pii: 1759091415568913. 

Annunziata I, Patterson A, D'azzo A. Isolation of mitochondria-associated er membranes (MAMs) and glycosphingolipid-enriched micro domains (GEMs) from brain tissues and neuronal cells. Methods Mol Biol 1264:25-33, 2015.

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 9(8):e104229, 2014.

Chen GY, Brown NK, Wu W, Khedri Z, Yu H, Chen X, Van De Vlekkert D, D'azzo A, Zheng P, Liu Y. Broad and direct interaction between tlr and siglec families of pattern recognition receptors and its regulation by NEU1. Elife 3:e04066, 2014.

Katorcha E, Makarava N, Savtchenko R, D'azzo A, Baskakov IV. Sialylation of prion protein controls the rate of prion amplification, the cross-species barrier, the ratio of prpsc glycoform and prion infectivity. PLoS Pathog 10(9):e1004366, 2014.

Bonten EJ, Annunziata I, D'azzo A. Lysosomal multienzyme complex: Pros and cons of working together. Cell Mol Life Sci 71(11):2017-32, 2014.

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Annunziata I, D'azzo A. Interorganellar membrane microdomains: Dynamic platforms in the control of calcium signaling and apoptosis. Cells 2(3):574-90, 2013.

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 8:114, 2013.

Annunziata I, Patterson A, D'azzo A. Mitochondria-associated er membranes (MAMs) and glycosphingolipid enriched micro domains (GEMs): Isolation from mouse brain. J Vis Exp(73):e50215, 2013.

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-beta secretion via deregulated lysosomal exocytosis. Nat Commun 4:2734, 2013.

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 1832(10):1784-92, 2013.

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 Lett587(9):1379-84, 2013.

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 20(2):267-74, 2012.

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 287(15):12159-71, 2012.

Baek RC, Broekman ML, Leroy SG, Tierney LA, Sandberg MA, D'azzo A, Seyfried TN, Sena-Esteves M. Aav-mediated gene delivery in adult GM1-gangliosidosis mice corrects lysosomal storage in cns and improves survival. PLoS One 5(10):e13468, 2010.

Monti E, Bonten E, D'azzo A, Bresciani R, Venerando B, Borsani G, Schauer R, Tettamanti G. Sialidases in vertebrates: A family of enzymes tailored for several cell functions. Adv Carbohydr Chem Biochem 64:403-79, 2010.

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 1802(2):259-68, 2010.

Zanoteli E, Van De Vlekkert D, Bonten EJ, Hu H, Mann L, Gomero EM, Harris AJ, Ghersi G, D'azzo A. Muscle degeneration in neuraminidase 1-deficient mice results from infiltration of the muscle fibers by expanded connective tissue. Biochim Biophys Acta 1802(7-8):659-72, 2010.

D'azzo A, Bonten E. Molecular mechanisms of pathogenesis in a glycosphingolipid and a glycoprotein storage disease. Biochem Soc Trans 38(6):1453-7, 2010.

Campos Y, Qiu X, Zanoteli E, Moshiach S, Vergani N, Bongiovanni A, Harris AJ, D'azzo A. Ozz-E3 ubiquitin ligase targets sarcomeric embryonic myosin heavy chain during muscle development. PLoS One 5(3):e9866, 2010.

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 36(3):500-11, 2009.

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 284(41):28430-41, 2009.

Yogalingam G, Bonten EJ, Van De Vlekkert D, Hu H, Moshiach S, Connell SA, D'azzo A. Neuraminidase 1 is a negative regulator of lysosomal exocytosis. Dev Cell 15(1):74-86, 2008.

D'azzo A, Tessitore A, Sano R. Gangliosides as apoptotic signals in er stress response. Cell Death Differ 13(3):404-14, 2006.

Wang D, Bonten EJ, Yogalingam G, Mann L, D'azzo A. Short-term, high dose enzyme replacement therapy in sialidosis mice. Mol Genet Metab 85(3):181-9, 2005.

Sano R, Tessitore A, Ingrassia A, D'azzo A. Chemokine-induced recruitment of genetically modified bone marrow cells into the cns of GM1-gangliosidosis mice corrects neuronal pathology. Blood 106(7):2259-68, 2005.

D'azzo A, Bongiovanni A, Nastasi T. E3 ubiquitin ligases as regulators of membrane protein trafficking and degradation. Traffic 6(6):429-41, 2005.

Bonten EJ, Wang D, Toy JN, Mann L, Mignardot A, Yogalingam G, D'azzo A. Targeting macrophages with baculovirus-produced lysosomal enzymes: Implications for enzyme replacement therapy of the glycoprotein storage disorder galactosialidosis. FASEB J 18(9):971-3, 2004.

Tessitore A, Del PMM, Sano R, Ma Y, Mann L, Ingrassia A, Laywell ED, Steindler DA, Hendershot LM, D'azzo A. GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis. Mol Cell 15(5):753-66, 2004.

Nastasi T, Bongiovanni A, Campos Y, Mann L, Toy JN, Bostrom J, Rottier R, Hahn C, Conaway JW, Harris AJ, D'azzo A. Ozz-E3, a muscle-specific ubiquitin ligase, regulates beta-catenin degradation during myogenesis. Dev Cell 6(2):269-82, 2004.

Cuervo AM, Mann L, Bonten EJ, D'azzo A, Dice JF. Cathepsin A regulates chaperone-mediated autophagy through cleavage of the lysosomal receptor. EMBO J 22(1):47-59, 2003.

D'azzo A. Gene transfer strategies for correction of lysosomal storage disorders. Acta Haematol 110(2-3):71-85, 2003.

Leimig T, Mann L, Martin Mdel P, Bonten E, Persons D, Knowles J, Allay JA, Cunningham J, Nienhuis AW, Smeyne R, D'azzo A. Functional amelioration of murine galactosialidosis by genetically modified bone marrow hematopoietic progenitor cells. Blood 99(9):3169-78, 2002.

De Geest N, Bonten E, Mann L, De Sousa-Hitzler J, Hahn C, D'azzo A. Systemic and neurologic abnormalities distinguish the lysosomal disorders sialidosis and galactosialidosis in mice. Hum Mol Genet 11(12):1455-64, 2002.

Bonten EJ, Arts WF, Beck M, Covanis A, Donati MA, Parini R, Zammarchi E, D'azzo A. Novel mutations in lysosomal neuraminidase identify functional domains and determine clinical severity in sialidosis. Hum Mol Genet 9(18):2715-25, 2000.

Hahn CN, Del Pilar Martin M, Zhou XY, Mann LW, D'azzo A. Correction of murine galactosialidosis by bone marrow-derived macrophages overexpressing human protective protein/cathepsin A under control of the colony-stimulating factor-1 receptor promoter. Proc Natl Acad Sci USA 95(25):14880-5, 1998.

Rottier RJ, Hahn CN, Mann LW, Del Pilar Martin M, Smeyne RJ, Suzuki K, D'azzo A. Lack of PPCA expression only partially coincides with lysosomal storage in galactosialidosis mice: Indirect evidence for spatial requirement of the catalytic rather than the protective function of PPCA. Hum Mol Genet 7(11):1787-94, 1998.

Van Der Spoel A, Bonten E, D'azzo A. Transport of human lysosomal neuraminidase to mature lysosomes requires protective protein/cathepsin A. EMBO J 17(6):1588-97, 1998.

Rudenko G, Bonten E, Hol WG, D'azzo A. The atomic model of the human protective protein/cathepsin a suggests a structural basis for galactosialidosis. Proc Natl Acad Sci USA 95(2):621-5, 1998.

Hahn CN, Del Pilar Martin M, Schroder M, Vanier MT, Hara Y, Suzuki K, Suzuki K, D'azzo A. Generalized cns disease and massive GM1-ganglioside accumulation in mice defective in lysosomal acid beta-galactosidase. Hum Mol Genet 6(2):205-11, 1997.

Bonten E, Van Der Spoel A, Fornerod M, Grosveld G D'azzo A. Characterization of human lysosomal neuraminidase defines the molecular basis of the metabolic storage disorder sialidosis. Genes Dev 10(24):3156-69, 1996.

Rudenko G, Bonten E, D'azzo A, Hol WG. Three-dimensional structure of the human 'protective protein': Structure of the precursor form suggests a complex activation mechanism. Structure3(11):1249-59, 1995.

Zhou XY, Morreau H, Rottier R, Davis D, Bonten E, Gillemans N, Wenger D, Grosveld FG, Doherty P, Suzuki K, Grosveld GC, D'azzo A. Mouse model for the lysosomal disorder galactosialidosis and correction of the phenotype with overexpressing erythroid precursor cells. Genes Dev 9(21):2623-34, 1995.

Galjart NJ, Gillemans N, Harris A, Van Der Horst GT, Verheijen FW, Galjaard H, D'azzo A. Expression of cdna encoding the human "protective protein" associated with lysosomal beta-galactosidase and neuraminidase: Homology to yeast proteases. Cell 54(6):755-64, 1988.

D'azzo A, Hoogeveen A, Reuser AJ, Robinson D, Galjaard H. Molecular defect in combined beta-galactosidase and neuraminidase deficiency in man. Proc Natl Acad Sci USA 79(15):4535-9, 1982.

Last update: April 2021