A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages

Pereira, Mafalda M. A.; Mahú, Inês; Seixas, Elsa; Martinéz-Sánchez, Noelia; Kubasova, Nadiya; Pirzgalska, Roksana M; Cohen, Paul; Dietrich, Marcelo O; López, Miguel; Bernardes, Gonçalo J. L.; Domingos, Ana I.

Publicação

A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages

2017-04-03Artigo científico

dc.contributor.author	Pereira, Mafalda M. A.
dc.contributor.author	Mahú, Inês
dc.contributor.author	Seixas, Elsa
dc.contributor.author	Martinéz-Sánchez, Noelia
dc.contributor.author	Kubasova, Nadiya
dc.contributor.author	Pirzgalska, Roksana M
dc.contributor.author	Cohen, Paul
dc.contributor.author	Dietrich, Marcelo O
dc.contributor.author	López, Miguel
dc.contributor.author	Bernardes, Gonçalo J. L.
dc.contributor.author	Domingos, Ana I.
dc.date.accessioned	2017-04-10T14:21:49Z
dc.date.available	2017-04-10T14:21:49Z
dc.date.issued	2017-04-03
dc.description.abstract	Conditional expression of diphtheria toxin receptor (DTR) is widely used for tissue-specific ablation of cells. However, diphtheria toxin (DT) crosses the blood-brain barrier, which limits its utility for ablating peripheral cells using Cre drivers that are also expressed in the central nervous system (CNS). Here we report the development of a brain-sparing DT, termed BRAINSPAReDT, for tissue-specific genetic ablation of cells outside the CNS. We prevent blood-brain barrier passage of DT through PEGylation, which polarizes the molecule and increases its size. We validate BRAINSPAReDT with regional genetic sympathectomy: BRAINSPAReDT ablates peripheral but not central catecholaminergic neurons, thus avoiding the Parkinson-like phenotype associated with full dopaminergic depletion. Regional sympathectomy compromises adipose tissue thermogenesis, and renders mice susceptible to obesity. We provide a proof of principle that BRAINSPAReDT can be used for Cre/DTR tissue-specific ablation outside the brain using CNS drivers, while consolidating the link between adiposity and the sympathetic nervous system.	pt_PT
dc.description.sponsorship	Fundação para a Ciência e Tecnologia grant: (PTDC/BIM-MET/3750/2014); European Molecular Biology Organization (EMBO); European Community’s Seventh Framework Programme (FP7/2007-2013) under agreement no. (281854—the ObERStress project); MINECO co-funded by the FEDER Program of EU: (ML: SAF20015-71026-R); Xunta de Galicia grant: (ML: 2015-CP079); Instituto Gulbenkian de Ciência; Royal Society University.	pt_PT
dc.description.version	info:eu-repo/semantics/publishedVersion	pt_PT
dc.identifier.citation	Pereira, M. M. A. et al. A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages. Nat. Commun. 8, 14967 doi: 10.1038/ncomms14967 (2017).	pt_PT
dc.identifier.doi	10.1038/ncomms14967	pt_PT
dc.identifier.uri	http://hdl.handle.net/10400.7/746
dc.language.iso	eng	pt_PT
dc.peerreviewed	yes	pt_PT
dc.publisher	Nature Publishing Group	pt_PT
dc.relation.publisherversion	http://www.nature.com/articles/ncomms14967	pt_PT
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/	pt_PT
dc.subject	Chemical modification	pt_PT
dc.subject	Molecular neuroscience	pt_PT
dc.subject	Neuroimmunology	pt_PT
dc.subject	Peripheral nervous system	pt_PT
dc.title	A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages	pt_PT
dc.type	journal article
dspace.entity.type	Publication
oaire.citation.endPage	10	pt_PT
oaire.citation.startPage	1	pt_PT
oaire.citation.title	Nature Communications	pt_PT
oaire.citation.volume	8	pt_PT
rcaap.rights	openAccess	pt_PT
rcaap.type	article	pt_PT