Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia

A Zanardi, A Conti, M Cremonesi, P D'Adamo, Maria Enrica Gilberti, P Apostoli, CV Cannistraci, Alberto Piperno, Samuel David, M Alessio

Research output: Contribution to journalArticle

Abstract

Aceruloplasminemia is a monogenic disease caused by mutations in the ceruloplasmin gene that result in loss of protein ferroxidase activity. Ceruloplasmin plays a role in iron homeostasis, and its activity impairment leads to iron accumulation in liver, pancreas, and brain. Iron deposition promotes diabetes, retinal degeneration, and progressive neurodegeneration. Current therapies mainly based on iron chelation, partially control systemic iron deposition but are ineffective on neurodegeneration. We investigated the potential of ceruloplasmin replacement therapy in reducing the neurological pathology in the ceruloplasmin-knockout (CpKO) mouse model of aceruloplasminemia. CpKO mice were intraperitoneal administered for 2 months with human ceruloplasmin that was able to enter the brain inducing replacement of the protein levels and rescue of ferroxidase activity. Ceruloplasmin-treated mice showed amelioration of motor incoordination that was associated with diminished loss of Purkinje neurons and reduced brain iron deposition, in particular in the choroid plexus. Computational analysis showed that ceruloplasmin-treated CpKO mice share a similar pattern with wild-type animals, highlighting the efficacy of the therapy. These data suggest that enzyme replacement therapy may be a promising strategy for the treatment of aceruloplasminemia.
Original languageEnglish
Pages (from-to)91-106
Number of pages16
JournalEMBO Molecular Medicine
Volume10
Issue number1
Publication statusPublished - 2018

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Ceruloplasmin
Iron
Knockout Mice
Therapeutics
Brain
Familial apoceruloplasmin deficiency
Enzyme Replacement Therapy
Retinal Degeneration
Choroid Plexus
Wild Animals
Purkinje Cells
Ataxia
Pancreas
Proteins
Homeostasis
Pathology

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Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia. / Zanardi, A; Conti, A; Cremonesi, M; D'Adamo, P; Gilberti, Maria Enrica; Apostoli, P; Cannistraci, CV; Piperno, Alberto; David, Samuel; Alessio, M.

In: EMBO Molecular Medicine, Vol. 10, No. 1, 2018, p. 91-106.

Research output: Contribution to journalArticle

Zanardi, A, Conti, A, Cremonesi, M, D'Adamo, P, Gilberti, ME, Apostoli, P, Cannistraci, CV, Piperno, A, David, S & Alessio, M 2018, 'Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia', EMBO Molecular Medicine, vol. 10, no. 1, pp. 91-106.
Zanardi, A ; Conti, A ; Cremonesi, M ; D'Adamo, P ; Gilberti, Maria Enrica ; Apostoli, P ; Cannistraci, CV ; Piperno, Alberto ; David, Samuel ; Alessio, M. / Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia. In: EMBO Molecular Medicine. 2018 ; Vol. 10, No. 1. pp. 91-106.
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abstract = "Aceruloplasminemia is a monogenic disease caused by mutations in the ceruloplasmin gene that result in loss of protein ferroxidase activity. Ceruloplasmin plays a role in iron homeostasis, and its activity impairment leads to iron accumulation in liver, pancreas, and brain. Iron deposition promotes diabetes, retinal degeneration, and progressive neurodegeneration. Current therapies mainly based on iron chelation, partially control systemic iron deposition but are ineffective on neurodegeneration. We investigated the potential of ceruloplasmin replacement therapy in reducing the neurological pathology in the ceruloplasmin-knockout (CpKO) mouse model of aceruloplasminemia. CpKO mice were intraperitoneal administered for 2 months with human ceruloplasmin that was able to enter the brain inducing replacement of the protein levels and rescue of ferroxidase activity. Ceruloplasmin-treated mice showed amelioration of motor incoordination that was associated with diminished loss of Purkinje neurons and reduced brain iron deposition, in particular in the choroid plexus. Computational analysis showed that ceruloplasmin-treated CpKO mice share a similar pattern with wild-type animals, highlighting the efficacy of the therapy. These data suggest that enzyme replacement therapy may be a promising strategy for the treatment of aceruloplasminemia.",
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AB - Aceruloplasminemia is a monogenic disease caused by mutations in the ceruloplasmin gene that result in loss of protein ferroxidase activity. Ceruloplasmin plays a role in iron homeostasis, and its activity impairment leads to iron accumulation in liver, pancreas, and brain. Iron deposition promotes diabetes, retinal degeneration, and progressive neurodegeneration. Current therapies mainly based on iron chelation, partially control systemic iron deposition but are ineffective on neurodegeneration. We investigated the potential of ceruloplasmin replacement therapy in reducing the neurological pathology in the ceruloplasmin-knockout (CpKO) mouse model of aceruloplasminemia. CpKO mice were intraperitoneal administered for 2 months with human ceruloplasmin that was able to enter the brain inducing replacement of the protein levels and rescue of ferroxidase activity. Ceruloplasmin-treated mice showed amelioration of motor incoordination that was associated with diminished loss of Purkinje neurons and reduced brain iron deposition, in particular in the choroid plexus. Computational analysis showed that ceruloplasmin-treated CpKO mice share a similar pattern with wild-type animals, highlighting the efficacy of the therapy. These data suggest that enzyme replacement therapy may be a promising strategy for the treatment of aceruloplasminemia.

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