Ceruloplasmin Regulates Iron Levels in the CNS and Prevents Free Radical Injury

Abstract

Ceruloplasmin is a ferroxidase that oxidizes toxic ferrous iron to its nontoxic ferric form. We have previously reported that a glycosylphosphatidylinositol-anchored form of ceruloplasmin is expressed in the mammalian CNS. To better understand the role of ceruloplasmin in iron homeostasis in the CNS, we generated a ceruloplasmin gene-deficient (Cp(-/-)) mouse. Adult Cp(-/-) mice showed increased iron deposition in several regions of the CNS such as the cerebellum and brainstem. Increased lipid peroxidation was also seen in some CNS regions. Cerebellar cells from neonatal Cp(-/-) mice were also more susceptible to oxidative stress in vitro. Cp(-/-) mice showed deficits in motor coordination that were associated with a loss of brainstem dopaminergic neurons. These results indicate that ceruloplasmin plays an important role in maintaining iron homeostasis in the CNS and in protecting the CNS from iron-mediated free radical injury. Therefore, the antioxidant effects of ceruloplasmin could have important implications for various neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease in which iron deposition is known to occur.

Oxidation-induced Structural Changes of Ceruloplasmin Foster NGR Motif Deamidation That Promotes Integrin Binding and Signaling

“…The observed loss of ferroxidase activity of Cp aged in AD CSF suggests that changes in the Cp structure can be fostered also ex vivo. Given the role of Cp, ferroxidase activity reduction may affect the iron homeostasis (38), causing an increase in iron retention as seen in (17,26,28).…”

Proteinograma e teores de cobre, ferro e zinco no soro sanguíneo de ovelhas da raça Santa Inês com mastite experimental por Staphylococcus aureus

“…A elevação do teor sérico de ceruloplasmina, seis vezes superior ao observado no momento controle, coincidiu com a maior gravidade do quadro clí-nico 24h p.i. O aumento da concentração desta proteína pode ser justificada por sua ação antiinflamatória e biocatalisadora (Chassagne et al 1998, Patel et al 2002. Apesar de não ser encontrada na literatura consultada informação quanto à resposta da ceruloplasmina em caso de mastite em ovelha infectada por S. aureus, há relatos de elevação desta PFA em outras enfermidades nesta espé-cie, bem como em bovinos (Chassagne et al 1998, Pfeffer & Rogers 1989, Pfeffer et al 1993, Fagliari et al 2003.…”

Redox Cycling in Iron Uptake, Efflux, and Trafficking

“…GPI provides a membrane anchor for the Cp so that, when "secreted" from the glial cell, the Cp remains tethered to the exocytoplasmic surface in an orientation equivalent to that of Hp in the enterocyte or Fet3 in the yeast PM. The precise role of GPI-Cp in the CNS is not fully understood, although it is linked to its role in iron efflux from astrocytes (65); what is clear, however, is that its absence correlates to a variety of neuropathologies, including neuronal death (66,67).…”