Cargando…

Treatment with the Bacterial Toxin CNF1 Selectively Rescues Cognitive and Brain Mitochondrial Deficits in a Female Mouse Model of Rett Syndrome Carrying a MeCP2-Null Mutation

Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene and a major cause of intellectual disability in females. No cure exists for RTT. We previously reported that the behavioural phenotype and brain mitochondria dysfunction are widely rescued by a single...

Descripción completa

Detalles Bibliográficos
Autores principales: Urbinati, Chiara, Cosentino, Livia, Germinario, Elena Angela Pia, Valenti, Daniela, Vigli, Daniele, Ricceri, Laura, Laviola, Giovanni, Fiorentini, Carla, Vacca, Rosa Anna, Fabbri, Alessia, De Filippis, Bianca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269120/
https://www.ncbi.nlm.nih.gov/pubmed/34201747
http://dx.doi.org/10.3390/ijms22136739
_version_ 1783720505286590464
author Urbinati, Chiara
Cosentino, Livia
Germinario, Elena Angela Pia
Valenti, Daniela
Vigli, Daniele
Ricceri, Laura
Laviola, Giovanni
Fiorentini, Carla
Vacca, Rosa Anna
Fabbri, Alessia
De Filippis, Bianca
author_facet Urbinati, Chiara
Cosentino, Livia
Germinario, Elena Angela Pia
Valenti, Daniela
Vigli, Daniele
Ricceri, Laura
Laviola, Giovanni
Fiorentini, Carla
Vacca, Rosa Anna
Fabbri, Alessia
De Filippis, Bianca
author_sort Urbinati, Chiara
collection PubMed
description Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene and a major cause of intellectual disability in females. No cure exists for RTT. We previously reported that the behavioural phenotype and brain mitochondria dysfunction are widely rescued by a single intracerebroventricular injection of the bacterial toxin CNF1 in a RTT mouse model carrying a truncating mutation of the MeCP2 gene (MeCP2-308 mice). Given the heterogeneity of MECP2 mutations in RTT patients, we tested the CNF1 therapeutic efficacy in a mouse model carrying a null mutation (MeCP2-Bird mice). CNF1 selectively rescued cognitive defects, without improving other RTT-related behavioural alterations, and restored brain mitochondrial respiratory chain complex activity in MeCP2-Bird mice. To shed light on the molecular mechanisms underlying the differential CNF1 effects on the behavioural phenotype, we compared treatment effects on relevant signalling cascades in the brain of the two RTT models. CNF1 provided a significant boost of the mTOR activation in MeCP2-308 hippocampus, which was not observed in the MeCP2-Bird model, possibly explaining the differential effects of CNF1. These results demonstrate that CNF1 efficacy depends on the mutation beared by MeCP2-mutated mice, stressing the need of testing potential therapeutic approaches across RTT models.
format Online
Article
Text
id pubmed-8269120
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-82691202021-07-10 Treatment with the Bacterial Toxin CNF1 Selectively Rescues Cognitive and Brain Mitochondrial Deficits in a Female Mouse Model of Rett Syndrome Carrying a MeCP2-Null Mutation Urbinati, Chiara Cosentino, Livia Germinario, Elena Angela Pia Valenti, Daniela Vigli, Daniele Ricceri, Laura Laviola, Giovanni Fiorentini, Carla Vacca, Rosa Anna Fabbri, Alessia De Filippis, Bianca Int J Mol Sci Article Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene and a major cause of intellectual disability in females. No cure exists for RTT. We previously reported that the behavioural phenotype and brain mitochondria dysfunction are widely rescued by a single intracerebroventricular injection of the bacterial toxin CNF1 in a RTT mouse model carrying a truncating mutation of the MeCP2 gene (MeCP2-308 mice). Given the heterogeneity of MECP2 mutations in RTT patients, we tested the CNF1 therapeutic efficacy in a mouse model carrying a null mutation (MeCP2-Bird mice). CNF1 selectively rescued cognitive defects, without improving other RTT-related behavioural alterations, and restored brain mitochondrial respiratory chain complex activity in MeCP2-Bird mice. To shed light on the molecular mechanisms underlying the differential CNF1 effects on the behavioural phenotype, we compared treatment effects on relevant signalling cascades in the brain of the two RTT models. CNF1 provided a significant boost of the mTOR activation in MeCP2-308 hippocampus, which was not observed in the MeCP2-Bird model, possibly explaining the differential effects of CNF1. These results demonstrate that CNF1 efficacy depends on the mutation beared by MeCP2-mutated mice, stressing the need of testing potential therapeutic approaches across RTT models. MDPI 2021-06-23 /pmc/articles/PMC8269120/ /pubmed/34201747 http://dx.doi.org/10.3390/ijms22136739 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Urbinati, Chiara
Cosentino, Livia
Germinario, Elena Angela Pia
Valenti, Daniela
Vigli, Daniele
Ricceri, Laura
Laviola, Giovanni
Fiorentini, Carla
Vacca, Rosa Anna
Fabbri, Alessia
De Filippis, Bianca
Treatment with the Bacterial Toxin CNF1 Selectively Rescues Cognitive and Brain Mitochondrial Deficits in a Female Mouse Model of Rett Syndrome Carrying a MeCP2-Null Mutation
title Treatment with the Bacterial Toxin CNF1 Selectively Rescues Cognitive and Brain Mitochondrial Deficits in a Female Mouse Model of Rett Syndrome Carrying a MeCP2-Null Mutation
title_full Treatment with the Bacterial Toxin CNF1 Selectively Rescues Cognitive and Brain Mitochondrial Deficits in a Female Mouse Model of Rett Syndrome Carrying a MeCP2-Null Mutation
title_fullStr Treatment with the Bacterial Toxin CNF1 Selectively Rescues Cognitive and Brain Mitochondrial Deficits in a Female Mouse Model of Rett Syndrome Carrying a MeCP2-Null Mutation
title_full_unstemmed Treatment with the Bacterial Toxin CNF1 Selectively Rescues Cognitive and Brain Mitochondrial Deficits in a Female Mouse Model of Rett Syndrome Carrying a MeCP2-Null Mutation
title_short Treatment with the Bacterial Toxin CNF1 Selectively Rescues Cognitive and Brain Mitochondrial Deficits in a Female Mouse Model of Rett Syndrome Carrying a MeCP2-Null Mutation
title_sort treatment with the bacterial toxin cnf1 selectively rescues cognitive and brain mitochondrial deficits in a female mouse model of rett syndrome carrying a mecp2-null mutation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269120/
https://www.ncbi.nlm.nih.gov/pubmed/34201747
http://dx.doi.org/10.3390/ijms22136739
work_keys_str_mv AT urbinatichiara treatmentwiththebacterialtoxincnf1selectivelyrescuescognitiveandbrainmitochondrialdeficitsinafemalemousemodelofrettsyndromecarryingamecp2nullmutation
AT cosentinolivia treatmentwiththebacterialtoxincnf1selectivelyrescuescognitiveandbrainmitochondrialdeficitsinafemalemousemodelofrettsyndromecarryingamecp2nullmutation
AT germinarioelenaangelapia treatmentwiththebacterialtoxincnf1selectivelyrescuescognitiveandbrainmitochondrialdeficitsinafemalemousemodelofrettsyndromecarryingamecp2nullmutation
AT valentidaniela treatmentwiththebacterialtoxincnf1selectivelyrescuescognitiveandbrainmitochondrialdeficitsinafemalemousemodelofrettsyndromecarryingamecp2nullmutation
AT viglidaniele treatmentwiththebacterialtoxincnf1selectivelyrescuescognitiveandbrainmitochondrialdeficitsinafemalemousemodelofrettsyndromecarryingamecp2nullmutation
AT riccerilaura treatmentwiththebacterialtoxincnf1selectivelyrescuescognitiveandbrainmitochondrialdeficitsinafemalemousemodelofrettsyndromecarryingamecp2nullmutation
AT laviolagiovanni treatmentwiththebacterialtoxincnf1selectivelyrescuescognitiveandbrainmitochondrialdeficitsinafemalemousemodelofrettsyndromecarryingamecp2nullmutation
AT fiorentinicarla treatmentwiththebacterialtoxincnf1selectivelyrescuescognitiveandbrainmitochondrialdeficitsinafemalemousemodelofrettsyndromecarryingamecp2nullmutation
AT vaccarosaanna treatmentwiththebacterialtoxincnf1selectivelyrescuescognitiveandbrainmitochondrialdeficitsinafemalemousemodelofrettsyndromecarryingamecp2nullmutation
AT fabbrialessia treatmentwiththebacterialtoxincnf1selectivelyrescuescognitiveandbrainmitochondrialdeficitsinafemalemousemodelofrettsyndromecarryingamecp2nullmutation
AT defilippisbianca treatmentwiththebacterialtoxincnf1selectivelyrescuescognitiveandbrainmitochondrialdeficitsinafemalemousemodelofrettsyndromecarryingamecp2nullmutation