The group is focused on the identification of proteins differentially expressed or post- translationally modified in pathological conditions, in the fields of onco- and neuro-proteomics. Starting from these approaches Proteome biochemistry Unit developed dedicated research lines.
Ceruloplasmin (Cp) in neurodegeneration
Cp is a ferroxidase that plays a role in iron-homeostasis. In the cerebrospinal fluid (CSF) of Parkinson patients researchers found oxidized Cp. Oxidation inhibits Cp function contributing to neurodegeneration by cellular iron accumulation. Pro-oxidant CSFs promote Cp deamidation in NGR-motifs resulting in an integrin-binding gain of function able to transduce intracellular signals. The group is evaluating the effect that modified Cp may exert on blood-CSF-barrier alterations in neurodegeneration.
Cp-enzyme replacement therapy (ERT) in Acerulolasminemia (Acp)
Mutations in Cp gene, resulting in absence of the protein, are responsible for Acp, a rare genetic disease characterized inter alia by iron accumulation in brain that promotes neurodegeneration. No therapies are available for the neurological symptoms. The unit is studying the potential of Cp-ERT in reducing the neurodegeneration in the CpKO mouse model of Acp. Administered Cp is able to enter the brain replacing protein levels and ferroxidase activity. Treated mice show amelioration in neurological symptoms, suggesting that Cp-ERT may be a strategy for Acp treatment.
ADAM10 in colorectal cancer (Crc)
In the sera of Crc patients the group identified auto-Ab against an aberrant immature isoform of ADAM10, a metalloprotease involved in tumor progression and invasion. Auto-Ab anti-ADAM10 are associated with a favorable prognosis, thus reduction of ADAM10 activity could be a therapeutic opportunity. This unit is studying the mechanisms responsible for the aberrant processing and surface expression of the immature ADAM10 that might be a fingerprint of less aggressive tumor. To prove the potential of ADAM10 targeted therapy, new ADAM10 inhibitors are being tested.
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. 2018, in press.
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.
Álvarez-Fernández SM, Barbariga M, Cannizzaro L, Cannistraci CV, Hurley L, Zanardi A, Conti A, Sanvito F, Innocenzi A, Pecorelli N, Braga M, Alessio M. Serological immune response against ADAM10 pro-domain is associated with favourable prognosis in stage III colorectal cancer patients. Oncotarget 2016 Nov 29;7(48):80059-80076.
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.
Mignogna ML, Giannandrea M, Gurgone A, Fanelli F, Raimondi F, Mapelli L, Bassani S, Fang H, van Anken E, Alessio M, Passafaro M, Gatti S, Esteban JA, Huganir R, and D'Adamo P. The Intellectual Disability protein RAB39B regulates selectively GluA2 trafficking determining synaptic AMPAR composition. Nature Communications 2015 Mar 18;6:6504.
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.
De Monte L, Sanvito F, Olivieri S, Viganò F, Doglioni C, Frasson M, Braga M, Bachi A, Dellabona P, Protti MP and Alessio M. Serological immunoreactivity against colon cancer proteome varies upon disease progression. J. Proteome Res. 2008 Feb;7(2):504-14.
Scielzo C, Ghia P, Conti A, Bachi A, Guida G, Geuna M, Alessio M and Caligaris-Cappio F. HS1 protein is differentially expressed in chronic lymphocytic leukemia patient subsets with good or poor prognoses. J. Clin. Invest. 2005 Jun 1;115(6):1644–1650.
Anelli T, Alessio M, Mezghrani A, Simmen T, Talamo F, Bachi A, Sitia. ERp44, a novel endoplasmic reticulum folding assistant of the thioredoxin family. EMBO J. 2002 Feb 15;21(4):835-44.