Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia
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...
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doaj-103872c1349b451ebfa94b45f959766b2021-08-02T06:47:02ZengWileyEMBO Molecular Medicine1757-46761757-46842018-01-011019110610.15252/emmm.201708361Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemiaAlan Zanardi0Antonio Conti1Marco Cremonesi2Patrizia D'Adamo3Enrica Gilberti4Pietro Apostoli5Carlo Vittorio Cannistraci6Alberto Piperno7Samuel David8Massimo Alessio9Proteome Biochemistry Division of Genetics and Cell Biology IRCCS‐San Raffaele Scientific Institute Milan ItalyProteome Biochemistry Division of Genetics and Cell Biology IRCCS‐San Raffaele Scientific Institute Milan ItalyProteome Biochemistry Division of Genetics and Cell Biology IRCCS‐San Raffaele Scientific Institute Milan ItalyMolecular Genetics of Intellectual Disabilities Division of Neuroscience IRCCS‐San Raffaele Scientific Institute Milan ItalyUnit of Occupational Health and Industrial Hygiene Department of Medical and Surgical Specialties, Radiological Sciences and Public Health University of Brescia Brescia ItalyUnit of Occupational Health and Industrial Hygiene Department of Medical and Surgical Specialties, Radiological Sciences and Public Health University of Brescia Brescia ItalyBiomedical Cybernetics Group Biotechnology Center (BIOTEC) Center for Molecular and Cellular Bioengineering (CMCB) Department of Physics Technische Universität Dresden Dresden GermanySchool of Medicine and Surgery University of Milano Bicocca Monza ItalyCenter for Research in Neuroscience The Research Institute of The McGill University Health Center Montreal QC CanadaProteome Biochemistry Division of Genetics and Cell Biology IRCCS‐San Raffaele Scientific Institute Milan ItalyAbstract 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.https://doi.org/10.15252/emmm.201708361aceruloplasminemiaceruloplasminenzyme replacement therapyneurodegeneration with brain iron accumulation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alan Zanardi Antonio Conti Marco Cremonesi Patrizia D'Adamo Enrica Gilberti Pietro Apostoli Carlo Vittorio Cannistraci Alberto Piperno Samuel David Massimo Alessio |
spellingShingle |
Alan Zanardi Antonio Conti Marco Cremonesi Patrizia D'Adamo Enrica Gilberti Pietro Apostoli Carlo Vittorio Cannistraci Alberto Piperno Samuel David Massimo Alessio Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia EMBO Molecular Medicine aceruloplasminemia ceruloplasmin enzyme replacement therapy neurodegeneration with brain iron accumulation |
author_facet |
Alan Zanardi Antonio Conti Marco Cremonesi Patrizia D'Adamo Enrica Gilberti Pietro Apostoli Carlo Vittorio Cannistraci Alberto Piperno Samuel David Massimo Alessio |
author_sort |
Alan Zanardi |
title |
Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia |
title_short |
Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia |
title_full |
Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia |
title_fullStr |
Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia |
title_full_unstemmed |
Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia |
title_sort |
ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia |
publisher |
Wiley |
series |
EMBO Molecular Medicine |
issn |
1757-4676 1757-4684 |
publishDate |
2018-01-01 |
description |
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. |
topic |
aceruloplasminemia ceruloplasmin enzyme replacement therapy neurodegeneration with brain iron accumulation |
url |
https://doi.org/10.15252/emmm.201708361 |
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