title: Ceruloplasmin functional changes in Parkinson's disease-cerebrospinal fluid.
abstract: BACKGROUND
  Ceruloplasmin, a ferroxidase present in cerebrospinal fluid (CSF), plays a role in iron homeostasis protecting tissues from oxidative damage. Its reduced enzymatic activity was reported in Parkinson's disease (PD) contributing to the pathological iron accumulation. We previously showed that ceruloplasmin is modified by oxidation in vivo, and, in addition, in vitro by deamidation of specific NGR-motifs that foster the gain of integrin-binding function. Here we investigated whether the loss of ceruloplasmin ferroxidase activity in the CSF of PD patients was accompanied by NGR-motifs deamidation and gain of function.
  
  
  RESULTS
  We have found that endogenous ceruloplasmin in the CSF of PD patients showed structural changes, deamidation of the (962)NGR-motif which is usually hidden within the ceruloplasmin structure, and the gain of integrin-binding function. These effects occur owing to the presence of abnormal levels of hydrogen peroxide we detected in the CSF of PD patients. Interestingly, the pathological CSF's environment of PD patients promoted the same modifications in the exogenously added ceruloplasmin, which in turn resulted in loss of ferroxidase-activity and acquisition of integrin-binding properties.
  
  
  CONCLUSIONS
  We show that in pathological oxidative environment of PD-CSF the endogenous ceruloplasmin, in addition to loss-of-ferroxidase function, is modified as to gain integrin-binding function. These findings, beside the known role of ceruloplasmin in iron homeostasis, might have important pathogenic implications due to the potential triggering of signals mediated by the unusual integrin binding in cells of central nervous system. Furthermore, there are pharmacological implications because, based on data obtained in murine models, the administration of ceruloplasmin has been proposed as potential therapeutic treatment of PD, however, the observed CSF's pro-oxidant properties raise the possibility that in human the ceruloplasmin-based therapeutic approach might not be efficacious.
authors.affiliation: Proteome Biochemistry, IRCCS-San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy. marco.barbariga@med.lu.se.|Present address: Translational Neurology group, Wallenberg Neuroscience Center, BMC A10, 221 84, Lund, Sweden. marco.barbariga@med.lu.se.
authors.forename: Marco
authors.initials: M
authors.lastname: Barbariga
authors.affiliation: Tumor Biology and Vascular Targeting, IRCCS-San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy. curnis.flavio@hsr.it.
authors.forename: Flavio
authors.initials: F
authors.lastname: Curnis
authors.affiliation: ProMiFa-Protein Microsequencing Facility, IRCCS-San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy. andolfo.annapaola@hsr.it.
authors.forename: Annapaola
authors.initials: A
authors.lastname: Andolfo
authors.affiliation: Proteome Biochemistry, IRCCS-San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy. zanardi.alan@hsr.it.|Vita-Salute San Raffaele University, via Olgettina 60, 20132, Milan, Italy. zanardi.alan@hsr.it.
authors.forename: Alan
authors.initials: A
authors.lastname: Zanardi
authors.affiliation: Proteome Biochemistry, IRCCS-San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy. lazzaro.massimo@hsr.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Lazzaro
authors.affiliation: Proteome Biochemistry, IRCCS-San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy. conti.antonio@hsr.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Conti
authors.affiliation: INSPE-Institute of Experimental Neurology, IRCCS-San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy. magnani.giuseppe@hsr.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Magnani
authors.affiliation: INSPE-Institute of Experimental Neurology, IRCCS-San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy. volonte.mariantonietta@hsr.it.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Volontè
authors.affiliation: INSPE-Institute of Experimental Neurology, IRCCS-San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy. ferrari.laura@hsr.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Ferrari
authors.affiliation: INSPE-Institute of Experimental Neurology, IRCCS-San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy. comi.giancarlo@hsr.it.|Vita-Salute San Raffaele University, via Olgettina 60, 20132, Milan, Italy. comi.giancarlo@hsr.it.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.affiliation: Tumor Biology and Vascular Targeting, IRCCS-San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy. corti.angelo@hsr.it.
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
authors.affiliation: Proteome Biochemistry, IRCCS-San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy. alessio.massimo@hsr.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Alessio
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002490:Central Nervous System / Q000378:metabolism; D002570:Ceruloplasmin / Q000134:cerebrospinal fluid*; D005260:Female; D006801:Humans; D007501:Iron / Q000134:cerebrospinal fluid; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000134:cerebrospinal fluid*; D017382:Reactive Oxygen Species / Q000134:cerebrospinal fluid
chemical_list: D017382:Reactive Oxygen Species; D007501:Iron; D002570:Ceruloplasmin