Omics Sciences
Proteome biochemistry
Starting from the approach of the identification of proteins differentially expressed in neurodegenerative conditions, the Proteome biochemistry Unit is now fully dedicated to the study of the physiopathology of the rare genetic disease aceruloplasminemia and to the development of therapeutic strategies.
Research activity
Physio-pathological role of Ceruloplasmin (Cp)
Cp is a ferroxidase that plays a role in iron-homeostasis. Mutations in Cp gene, resulting in absence of the protein, are responsible for Aceruloplasminemia (Acp), an ultra rare genetic disease characterized inter alia by iron accumulation in brain that promotes neurodegeneration. In the central nervous system Cp is mainly produced and secreted in the cerebrospinal fluid (CSF) by the choroid plexus epithelial cells that constitute the blood-CSF-barrier. By using both the CpKO mouse model of the disease and a Cp-deficient model of epithelia choroid plexus cells, the group is evaluating the effect that the absence of Cp may exert on the metabolism of this organ and on blood-CSF-barrier’s properties. Beside its enzymatic role Cp inhibits myeloperoxidase (MPO) an inflammation mediator expressed by microglial cells. Therefore, the Unit is studying the role of microglia MPO-mediated neuroinflammation in the neuronal damage in Acp.
Development of therapeutic strategies for the Aceruloplasminemia
Nowadays, no therapies are available for the neurological symptoms of the aceruloplasminemia. The unit is studying the potential of Cp-enzyme replacement therapy (ERT) in reducing both the systemic and the neurological symptoms in the CpKO mouse model of Acp. The Cp purified from industrial plasma processing waste fraction has been used for long time treatment. Administered Cp is able to replace protein levels and ferroxidase activity, also in the brain, inducing an amelioration of both systemic symptoms and neurodegeneration. Thus, suggesting that Cp-ERT may be a good strategy for Acp treatment also for human in mid- short-term. A sex-related variation in Cp tissue bioavailability has been highlighted, pointing to the possibility of sex-specific therapeutic regimens in the design of the future therapies for Acp.
To bypass in the future some of the limitation of a life-long ERT, a gene-therapy treatment is under investigation by using a liver-directed lentiviral approach in the Cp-deficient mouse model. The aim is to generate an endogenous factory of the protein able to recovery the liver and erythropoiesis defects but also to be efficacious on the brain damage.
Ziliotto N, Lencioni S, Cirinciani M, Zanardi A, Alessio M, Soldà G, Da Pozzo E, Asselta R, Caricasole A. Functional characterization of Ceruloplasmin population variants and real-world prevalence assessment of Aceruloplasminemia. eBiomedicine 113: 105625, 2025.
Belloli S, Monterisi C, Rainone P, Coliva A, Zanardi A, Conti A, Caricasole A, Moresco RM, Alessio M. Ceruloplasmin administration in the preclinical mouse model of aceruloplasminemia reveals a sex-related variation in biodistribution. Communications Biology, 8: 264, 2025.
Zanardi A, Nardini I, Raia S, Conti A, Ferrini B, D’Adamo P, Gilberti E, DePalma G, Belloli S, Monterisi C, Coliva A, Rainone P, Moresco RM, Mori F, Zurlo G, Scali C, Natali L, Pancanti A, Giovacchini P, Magherini G, Tovani G, Salvini L, Cicaloni V, Tinti C, Tinti L, Lana D, Magni G, Giovannini MG, Gringeri A, Caricasole A, Alessio M. New orphan disease therapies from the proteome of industrial plasma processing waste- a treatment for aceruloplasminemia. Communications Biology, 7: 140, 2024.
Mannella V, Chaabane L, Canu T, Zanardi A, Raia S, Conti A, Ferrini B, Caricasole A, Musco G, Alessio M. Lipid dysmetabolism in ceruloplasmin-deficient mice revealed both in vivo and ex vivo by MRI, MRS and NMR analyses. FEBS Open Bio , 14: 258-275, 2024.
Zanardi A, Barbariga M, Conti A, Vegliani F, Curnis F, Alessio M. Oxidized/deamidated-ceruloplasmin dysregulates choroid plexus epithelial cells functionality and barrier properties via RGD-recognizing integrin binding. Neurobiol Dis, 158: 105475, 2021.
Barbariga M, Zanardi A, Curnis F, Conti A, Boselli D, Di Terlizzi S, Alessio M. Ceruloplasmin oxidized and deamidated by Parkinson's disease cerebrospinal fluid induces epithelial cells proliferation arrest and apoptosis. Scientific Reports, 10:15507, 2020.
Piperno A & Alessio M. Aceruloplasminemia: waiting for an efficient therapy. Frontiers in Neuroscience 12:903, 2018.
Pelucchi S, Mariani R, Ravasi G, Pelloni I, Marano M, Tremolizzo L, Alessio M, Piperno A. Phenotypic heterogeneity in seven italian cases of aceruloplasminemia. Parkinsonism Relat Disord 51:36-42, 2018.
Zanardi A, Conti A, Cremonesi M, D'Adamo P, Gilberti E, Apostoli P, Cannistraci CV, Piperno A, David S, Alessio M. Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia. EMBO-Molecular Medicine 2018, 10:91-106.
Barbariga M, Curnis F, Andolfo A, Zanardi A, Lazzaro M, Conti A, Magnani G, Volontè MA, Ferrari L, Comi G, Corti A, Alessio M. Ceruloplasmin functional changes in Parkinson's disease-cerebrospinal fluid. Molecular Neurodegeneration 2015;10:59.
Lazzaro M, Bettegazzi B, Barbariga M, Codazzi F, Zacchetti D, Alessio M. Ceruloplasmin potentiates nitric oxide synthase activity and cytokine secretion in activated microglia. J NeuroInfl 11: 164, 2014.
Barbariga M, Curnis F, Spitaleri A, Andolfo A, Zucchelli C, Lazzaro M, Magnani G, Musco G, Corti A, Alessio M. Oxidation-induced structural changes of ceruloplasmin foster NGR-motifs deamidation that promote integrin binding and signalling. J Biol Chem 2014 Feb 7;289(6):3736-48.
Olivieri S, Conti A, Iannaccone S, Cannistraci CV, Campanella A, Barbariga M, Codazzi F, Pelizzoni I, Magnani G, Pesca M, Franciotta D, Cappa S, Alessio M. Ceruloplasmin oxidation, a feature of Parkinson’s disease cerebrospinal fluid, inhibits ferroxidase activity and promotes cellular iron retention. J. Neurosci. 2011 Dec 14;31(50):18568-77.
